PhenoFluorMix: Practical chemoselective deoxyfluorination of phenols

Article abstract of DOI:10.1021/ol5035518

A practical deoxyfluorination with novel deoxyfluorinating reagent PhenoFluorMix, a mixture of N,N'-1,3-bis(2,6-diisopropylphenyl)chloroimidazolium chloride and CsF, is presented. PhenoFluorMix overcomes the challenges associated with hydrolysis of PhenoFluor. PhenoFluorMix does not hydrolyze, is readily available on decagram scale, and is storable in air. In this paper, we demonstrate the practicality of the reagent and exhibit the deoxyfluorination of a variety of phenols and heterocycles.

Full text of DOI:10.1021/ol5035518

Letter
pubs.acs.org/OrgLett
PhenoFluorMix: Practical Chemoselective Deoxyfluorination of
Phenols
Teppei Fujimoto and Tobias Ritter*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
S
* Supporting Information
ABSTRACT: A practical deoxyfluorination with novel deox-
yfluorinating reagent PhenoFluorMix, a mixture of N,N′-1,3-
bis(2,6-diisopropylphenyl)chloroimidazolium chloride and
CsF, is presented. PhenoFluorMix overcomes the challenges
associated with hydrolysis of PhenoFluor. PhenoFluorMix
does not hydrolyze, is readily available on decagram scale, and is storable in air. In this paper, we demonstrate the practicality of
the reagent and exhibit the deoxyfluorination of a variety of phenols and heterocycles.
henoFluor is a commercially available, useful deoxyfluori-
Pnating reagent applicable to deoxyfluorination of a variety
of phenols and aliphatic alcohols.1,2 Especially in the
pharmaceutical and agrochemical industries, PhenoFluor can
be employed for rapid analogue synthesis. However, Pheno-
Fluor is moisture sensitive.1d Because PhenoFluor readily
hydrolyzes, it needs to be stored over the long term in a
protective atmosphere, such as in an N2-filled glovebox, which
reduces the practical utility of the reagent. Herein, we report
the novel deoxyfluorinating reagent PhenoFluorMix, which
overcomes the challenges associated with hydrolysis of
Figure 2. Effect of water on PhenoFluor and PhenoFluorMix.
PhenoFluor; in contrast to PhenoFluor, PhenoFluorMix does
not hydrolyze and can be dried prior to deoxyfluorination
(Figure 1). Conceptually, deoxyfluorination with PhenoFluor-
a
Table 1. Solvent Effect on Deoxyfluorination of Phenols
Mix is of fundamental interest by virtue of fluorination being
observed exclusively despite the presence of two equivalents of
chloride. A chemoselective halogenation reaction that proceeds
solvent
R = p-Ph (%)
R = p-OMe (%)
R = o-OMe (%)
DME
dioxane
diglyme
toluene
o-xylene
anisole
91 (100 °C)
53 (100 °C)
94
43
78
34
87
91
12
12
96
94
97
14
66 (140 °C)
27 (140 °C)
a
Yields were determined by 19F NMR with 1-fluoro-3-nitrobenzene as
an internal standard.
with fluoride but not with the other halides is uncommon; in
fact, fluorination is virtually always more difficult to achieve
than other halogenation reactions.3
Over the past five years, a variety of transition-metal-
catalyzed or -mediated fluorination reactions have been
developed.4−7 Many of them exhibit improvements with
Received: December 9, 2014
Published: January 26, 2015
Figure 1. Comparison of PhenoFluor with PhenoFluorMix.
© 2015 American Chemical Society
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DOI: 10.1021/ol5035518
Org. Lett. 2015, 17, 544−547

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Letter
Scheme 1. Deoxyfluorination with PhenoFluorMix
a
b
Products were volatile; yields were determined by 19F NMR with 1-fluoro-3-nitrobenzene as an internal standard. Reactions were performed in
c
xylene at 140 °C. Reaction time was 20 min: prolonged reaction time caused the decomposition of product.
respect to reaction conditions compared to conventional
reactions such as the Balz−Schiemann reaction. However,
with respect to practicality, we feel that fluorination reactions
require further development. For example, Ag-catalyzed
fluorination reported by our group requires the synthesis and
use of toxic aryl stannanes.5a Buchwald’s Pd-catalyzed
fluorination has a broad substrate scope including heterocycles,
but electron-rich substrates lacking an ortho substituent can
afford constitutional isomers.4f,s Cu-mediated or -catalyzed
fluorinations of aryl iodides,6b boronates,6c trifluoroborates,6d,g
and iodonium salts6f have been reported, but basic nitrogen-
containing heterocycles are challenging substrates for such
methods. Furthermore, reduced products generated by
protodehalogenations or protodemetalations can be a sub-
stantial challenge for several transition-metal-based fluorination
reactions because these products are difficult to separate during
purification.8
PhenoFluorMix is a 1:2 (by weight) mixture of N,N′-1,3-
bis(2,6-diisopropylphenyl)chloroimidazolium chloride9,1d and
CsF. In contrast to PhenoFluor, PhenoFluorMix, even when
wet or treated with water, does not hydrolyze to the urea
(Figure 2). Because of its stability toward moisture,
PhenoFluorMix is easily prepared on decagram scale on the
bench (also commercially available from Sigma-Aldrich, cat. no.
797537). Furthermore, unlike PhenoFluor, PhenoFluorMix is
storable under ambient atmosphere for at least 4 months
without any detectable decomposition. While the deoxyfluori-
nation with PhenoFluorMix still should be conducted under
anhydrous reaction conditions, PhenoFluorMix can be dried
prior to reaction, even if it adsorbs water during storage. We
obtained optimal yields of deoxyfluorination with Pheno-
FluorMix when the reagent was heated at 140 °C for 1 h under
vacuum immediately prior to use.
Deoxyfluorination of 4-hydroxybiphenyl with PhenoFluor-
Mix proceeds efficiently in several solvents including polar
solvents such as acetonitrile, DMF, and DMSO (see the
Supporting Information). However, we found that only ethers
and aromatic solvents worked well for electron-rich substrates
such as 4-methoxyphenol (Table 1). For substrates that are
both electron rich and sterically hindered, such as 2-
methoxyphenol, heating at 140 °C in xylene proved to be
most effective. Consequently, heating at 110 °C in dioxane or
toluene is a suitable reaction condition for most substrates,
whereas heating at 140 °C in xylene is effective for electron-rich
and sterically hindered substrates.
As shown in Scheme 1, a variety of phenols, including both
electron-deficient and electron-rich aromatics, as well as
heterocycles, are deoxyfluorinated with PhenoFluorMix.
Electron-rich phenols, such as p-alkoxy or p-alkylamino
phenols, the corresponding fluorides of which are often seen
in pharmaceuticals (6−8),10 and sterically hindered phenols (9,
10) underwent deoxyfluorination. Basic nitrogen-containing
heterocycles, such as pyridines (11, 12), imidazole (14),
isoquinoline (17), and quinolines (18, 19), are well tolerated,
so are aldehydes and ketones (4, 20), olefins (3), sulfides (13),
and halogens (4, 10). Deoxyfluorination with PhenoFluorMix
can be scaled up to gram scale (eq 1). Throughout our study,
fluorine constitutional isomers or reduced products were not
observed, which simplified purification. However, removal of
the resulting urea is inevitable. We also found that, as with
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DOI: 10.1021/ol5035518
Org. Lett. 2015, 17, 544−547

Organic Letters
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PhenoFluor,1a deoxyfluorination of phenols bearing a primary
or secondary carboxamide or carbamate is challenging. In
addition, five-membered heterocycles are generally unsuitable
substrates for the deoxyfluorination with PhenoFluorMix.
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The deoxyfluorination with PhenoFluorMix may not proceed
via in situ formation of PhenoFluor but via uronium
intermediates.1a We have obtained no evidence for the
formation of PhenoFluor and therefore believe that deoxy-
fluorination with PhenoFluorMix is not an in situ version of our
previously published PhenoFluor reaction. In view of the fact
that electron-rich phenols underwent deoxyfluorination, the
fluorination is likely not a simple SNAr reaction.11 Moreover,
the formation of aryl chlorides was not observed in the
reactions with PhenoFluorMix. Even in the presence of 10
equiv of CsCl, no chlorinated product was detected.
Conceptually, this chemoselectivity−deoxyfluorination versus
other deoxyhalogenation provides a fundamentally new
opportunity for C−F bond formation. While the origin of the
unusual selectivity is not yet apparent, PhenoFluorMix provides
a promising mechanistic entry to chemoselective fluorination
chemistry that other conventional and modern fluorination
reactions lack.
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deoxyfluorination with PhenoFluorMix. The novel reagent
does not easily hydrolyze, is readily available on decagram scale,
and is storable in air. The reaction can be performed on the
bench, does not require separation of fluorine constitutional
isomers or reduced product, and shows broad substrate scope
and high functional group tolerance. We believe Pheno-
FluorMix will provide facile access to practical late-stage
deoxyfluorination of small molecules and, currently, constitutes
one of the most general and practical reactions for late-stage
fluorination up to gram scale. Mechanistically, it could lead to a
better understanding of chemoselective fluorination chemistry.
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ASSOCIATED CONTENT
■
(5) For Ag-mediated or -catalyzed aryl fluoride synthesis, see:
(a) Furuya, T.; Strom, E. A.; Ritter, T. J. Am. Chem. Soc. 2009, 131,
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S
* Supporting Information
Detailed experimental procedures and spectroscopic character-
ization for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
(6) For Cu-mediated or -catalyzed aryl fluoride synthesis, see:
(a) Casitas, A.; Canta, M.; Sola, M.; Costas, M.; Ribas, X. J. Am. Chem.
̀
Corresponding Author
*E-mail: ritter@chemistry.harvard.edu.
Notes
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The authors declare the following competing financial
interest(s): T.R. may financially benefit from PhenoFluorMix
sales.
ACKNOWLEDGMENTS
■
We thank Constanze N. Neumann and Gregory B. Boursalian
for helpful discussions and Daiichi-Sankyo Co., Ltd., as well as
the NSF (CHE-0952753) for financial support.
Gen
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