Iron(II)-catalyzed benzylic fluorination

Article abstract of DOI:10.1021/ol400424s

Direct C-F functionalization of benzylic sp³ C-H bonds is a synthetic challenge that has yet to be propitiously overcome. A mild, one-pot synthesis of monofluorinated benzylic substrates is reported with commercially available iron(II) acetylacetonate and Selectfluor in good to excellent yields and selectivity. A convenient route to β-fluorinated products of 3-aryl ketones is also highlighted, providing a synthetic equivalent to the difficult to accomplish conjugate addition of fluoride to α,β-unsaturated ketones.

Full text of DOI:10.1021/ol400424s

ORGANIC
LETTERS
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Vol. XX, No. XX
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Iron(II)-Catalyzed Benzylic Fluorination
Steven Bloom, Cody Ross Pitts, Ryan Woltornist, Andrew Griswold,
Maxwell Gargiulo Holl, and Thomas Lectka*
Depatment of Chemistry, New Chemistry Building, Johns Hopkins University,
3400 North Charles Street, Baltimore, Maryland 21218, United States
lectka@jhu.edu
Received February 13, 2013
ABSTRACT
Direct CꢀF functionalization of benzylic sp3 CꢀH bonds is a synthetic challenge that has yet to be propitiously overcome. A mild, one-pot
synthesis of monofluorinated benzylic substrates is reported with commercially available iron(II) acetylacetonate and Selectfluor in good to
excellent yields and selectivity. A convenient route to β-fluorinated products of 3-aryl ketones is also highlighted, providing a synthetic equivalent
to the difficult to accomplish conjugate addition of fluoride to R,β-unsaturated ketones.
Practical, direct conversions of benzylic sp3 CꢀH bonds
intoCꢀF bondsoffer a potentially valuable addition tothe
category of CꢀH functionalization.1 Despite develop-
ments in site-specific oxygenation,2 amination,3 and other
halogenation methods,4 innate benzylic fluorination re-
mains an underdeveloped synthetic transformation,5 one
that relies heavily on the use of electrochemical methods6
or harsh, unselective reagents.7 Considering the growing
importance of fluorinated compounds in drug discovery, a
mild benzylic fluorination method may prove itself a useful
instrument for the medicinal chemist (e.g., potentially by
allowing inhibition of cytochrome P450 oxidation and
increasing the lifetime of a drug in vivo, among other
applications).8 Thus, our laboratory has recently taken an
interest in the development of a straightforward, metal-
catalyzed benzylic fluorination method.
€
(1) (a) Bruckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.
Res. 2012, 45, 826–839. (b) Labinger, J. A.; Bercaw, J. E. Nature 2002,
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417, 507–514. (c) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F.
Chem. Soc. Rev. 2011, 40, 4740–4761.
Both we (copper(I) bisimine, Selectfluor9) and the
Groves group (manganese porphyrin, fluoride ion,
iodosobenzene10) have reported unique catalytic systems
for the selective fluorination of aliphatic CꢀH bonds. In
our original copper system, we found that, although
applicable to a select few benzylic substrates, fluorination
proved somewhat difficult, notwithstanding the enhanced
reactivity of benzylic CꢀH bonds. Inspired by the oxi-
dation capabilities of certain biological catalysts, cost-
effectiveness, commercial availability, and/or ease of prep-
aration, we turned our attention to prospective iron
(2) (a) Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50,
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Racowski, J. M.; Sanford, M. S. Org. Lett. 2012, 14, 4094–4097.
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Weber, C. E.; Kasper, J. S.; Litant, I. Preparation, Properties and
Technology of Fluorine and Organic Fluoro Compounds; McGraw Hill:
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Organic Synthesis; Springer: Berlin, 1989; pp 135ꢀ168.
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10.1021/ol400424s
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catalysts (Scheme 1). Herein, we report our studies on a
catalyzed fluorination of benzylic substrates using an in-
expensive iron(II) salt, iron(II) acetylacetonate (Fe(acac)2),
and commercially available Selectfluor, under mild con-
ditions.
quantities of polyfluorinated products, often ring fluorina-
tion adducts.15 (2) A particularly interesting case, cymene,
1b, afforded fluorinated 2b exclusively, in direct contrast to
our previously reported copper system in which fluorina-
tion of the tertiary carbon is preferred. The formation of 2b
may be suggestiveof a changein mechanism whereby steric
constraints influence selectivity more so than trends in
radical stability. (3) Carbonyl-containing compounds de-
monstrated a notable shift in selectivity to benzylic fluo-
rination over an expected background reaction (Scheme 2).
Scheme 1. Effect of Catalyst on Substrate Scope
This unique system produces an array of benzylic fluori-
nated products in good to excellent yields and selectivity.
Moreover, we demonstrate the possibility for a strategi-
cally placed carbonyl group to result in site-specific fluo-
rination in the β-position, a potentially desirable synthetic
transformation. Further study of this and similar systems
may also provide a more clear understanding of haloge-
nase enzymes11 and potential use of ketones as directing
groups in CꢀH bond activation.12
Scheme 2. Iron(II)-Promoted Reversal in Selectivity
Noting previous success in the literature in CꢀH func-
tionalization by nonheme iron catalysts,13 we reasoned
that iron(II) salts could be effective for this transforma-
tion. We began our initial survey of iron salts as potential
catalysts with 3-phenylpropyl acetate 1a as a model sub-
strate. Among the iron salts screened, only Fe(acac)2
yielded the desired 3-fluoro-3-phenylpropyl acetate 2a.
The use of other iron salts, e.g., halides, sulfates, and
nitrates, failed to yield any fluorinated products under
our specified conditions. Perhaps this can be explained
by the fact that hard, polydentate O-donor ligands,
such as anionic acetylacetonate, allow easy access to
higher oxidation states, facilitating oxidative functionali-
zation. Accordingly, several late-transition-metal complexes
containing one or more acetylacetonate (acac) ligands
have appeared in recent years capable of CꢀH bond
activation.14
Traditionally, Selectfluor is known to react with carbonyl-
containing compounds to yield R-fluorinated products.16
For example, benzylacetone 1c reacts readily with Select-
fluor at elevated temperatures in acetonitrile to yield
R-fluorinated ketone (Scheme 2, path A). Interestingly
enough, under our catalytic conditions, benzylacetone reacts
at room temperature to give solely benzylic fluorinated
compound 2c (Scheme 2, path B). What is more, 2c would
be the retrosynthetic product of a 1,4-conjugate addition
of a fluoride anion to the analogous R,β-unsaturated
ketone (Figure 1), an attractive transformation in mod-
ern synthetic chemistry. In a similar instance, ibuprofen
methyl ester 1d affords predominantly benzylic fluorinated
2d under our conditions, potentially a pharmaceutically
Subsequently, we evaluated the scope of our system by
screening a series of benzylic substrates. To our satisfac-
tion, several substrates underwent sufficient benzylic fluo-
rination in good yieldsand in excellent selectivity (Table 1).
Some general observations were as follows: (1) Electron-
poor or more neutral alkyl benzenes proved most promis-
ing, whereas electron-rich aromatic systems leadtovarying
(11) For a review of halogenase enzymes, see: Vaillancourt, F. H.;
Yeh, E.; Vosburg, D. A.; Gameau-Tsodikova, S.; Walsh, C. T. Chem.
Rev. 2006, 106, 3364–3378.
Figure 1. Retrosynthetic 1,4-conjugate addition of fluoride.
(12) (a) Gandeepan, P.; Parthasarathy, K.; Cheng, C.-H. J. Am.
Chem. Soc. 2010, 132, 8569–8571. (b) Patureau, F. W.; Besset, T.;
Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1064–1067. (c) Xiao, B.;
Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 1466–
1474.
(13) (a) Xiaoli, S.; Li, J.; Huang, X.; Sun, C. Curr. Inorg. Chem. 2012,
2, 64–85. (b) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed.
2008, 47, 3317–3321.
(15) We have found that Selectfluor may fluorinate activated aro-
matic compounds in the absence of a catalyst.
(16) (a) Stavber, S.; Zupan, M. Tetrahedron Lett. 1996, 37, 3591–
3594. (b) Stavber, G.; Zupan, M.; Stavber, S. Synlett 2009, 4, 589–594.
(17) Geometry optimizations were performed using the Spartan ’10
program, Wavefunction, Inc.
(18) (a) Singh, R. P.; Shreeve, J. M. Chem. Commun. 2001, 13, 1196–
1197. (b) Advances in Organic Synthesis;Rahman, A.-U., Laali, K. K., Eds.;
Benthah: Hilversum, The Netherlands, 2006; Vol. 2, Modern Organofluo-
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1956–1959.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Survey of Benzylic Substrates
Scheme 3. Isodesmic Reaction for Dehydrofluorination to
Coumarin at B3LYP/6-311þþG**
interesting transformation, rather than the R-fluorinated
ketone.
Clearly, iron is crucial in reaction selectivity favoring
the benzylic position over chemistry at the more acidic
R-carbon. Moreso, the system is highly tolerable as aryl
ketones, esters, aliphatic ketones, amides, and other halo-
genatedsubstrates fluorinate with near equal propensity. It
is important to note that the majority of our substrates do
not undergo dehydrohalogenation upon workup, a com-
mon problem in benzylic halogenation. Surprisingly, β-
fluoro ketones proved particularly stable, contrary to our
previous finding that 2-fluorodihydrocoumarin 2f readily
dehydrofluorinates.
In this instance, analysis of an isodesmic reaction be-
tween a compound which readily dehydrofluorinates, fluo-
rodihydrocoumarin 2f, and one which does not, fluorodi-
hydrochalcone 2g, offers some insight (Scheme 3). At the
B3LYP/6-311þþG** level of theory, ΔE of the iso-
desmic reaction is ꢀ5.3 kcal/mol,17 suggesting a more
exothermic process, whereby fluorine is lost in favor of
desaturation and resultant gain in the aromatic character
of coumarin.
Nitrogen-containing compounds (such as amines) were
likewise problematic. In most cases, N-fluorination of the
starting compound inhibits desired functionalization,18
instead leading to N-oxidized products through a putative
iminium intermediate.19 We gathered that a compound in
which the presence of a carbonyl in concert with lowered
basicity of the nitrogen (e.g., through amide resonance)
would be primed for fluorination, such as 1h. Indeed, 1h
proved most amenable providing fluorinated 2h in 41%.
Future studies will seek to elucidate the mechanism of
this reaction through kinetic, isotopic, and spectroscopic
analysis. Additionally, efforts will be made in the way of
rendering the reaction enantioselective, an important goal
in direct fluorination methods, and determining the role of
carbonyls as potential directing groups for fluorination.
Acknowledgment. T.L. thanks the PRF-ACS and NSF
(CHE 113175) for support.
Supporting Information Available. Synthetic proce-
dures and the characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a Yields determined by 19F NMR using 3-chlorobenzotrifluoride as
an internal standard. b Isolated as the major benzylic product with minor
fluorinated isomers. All reactions were performed at room temperature
over 24 h unless otherwise stated.
The authors declare no competing financial interest.
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