Synthesis of highly fluorinated 2,2′-biphenols and 2,2′-bisanisoles

Article abstract of DOI:10.1021/ol101698a

Figure Presented. Multiply fluorine-substituted iodo anisoles are efficiently coupled in an Ullmann-type reaction to provide the corresponding bisanisoles. The coupling is selective and even tolerates bromo moieties. Subsequent deprotection of hydroxy gro

Full text of DOI:10.1021/ol101698a

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4288-4291
Synthesis of Highly Fluorinated
2,2′-Biphenols and 2,2′-Bisanisoles
Robert Francke,†,‡ Gregor Schnakenburg,§ and Siegfried R. Waldvogel*,†,‡
Kekule´ Institute for Organic Chemistry and Biochemistry, Bonn UniVersity,
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany, Institute for Organic Chemistry,
Johannes Gutenberg UniVersity Mainz, Duesbergweg 10-14, 55128 Mainz, Germany,
and X-ray Analysis Department, Institute for Inorganic Chemistry, Bonn UniVersity,
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
waldVogel@uni-mainz.de
Received July 21, 2010
ABSTRACT
Multiply fluorine-substituted iodo anisoles are efficiently coupled in an Ullmann-type reaction to provide the corresponding bisanisoles. The
coupling is selective and even tolerates bromo moieties. Subsequent deprotection of hydroxy groups gives access to highly fluorinated
biphenols.
Biphenols and related biaryls are very useful molecular
architectures in catalysis and asymmetric transformations.
These particular scaffolds provide chelating ligand systems
with an appropriate flexibility.1 Partial fluorination of these
biphenols and binaphthyls results in more acidic systems,
which imparts enhanced Lewis acidity to the metal com-
plexes.2 Consequently, several strategies have been realized
to obtain partially3,4 and perfluorinated binaphthyl deriva-
tives.5 The fluorination causes a considerable electronic
perturbation of the aromatic systems. This results in inverted
electrostatic potential surfaces compared to the nonfluorinated
species.6 Not surprisingly, such highly fluorinated compounds
are of interest for energy storage applications.7 Moreover,
the specific lipophilicity and metabolic stability of fluorinated
structures lead to significant application in drug development
and pharmaceutical applications.8 The strong polarization of
C,F-bonds also attracted research in liquid crystal develop-
ment.9 While the fluorinated naphthyl derivatives are well
investigated,2-5 the biphenyl congeners are only scarcely
treated.
† Kekule´ Institute for Organic Chemistry and Biochemistry, Bonn
University.
‡ Johannes Gutenberg University Mainz.
§ Institute for Inorganic Chemistry, Bonn University.
A direct oxidative coupling of fluoro phenols to the
corresponding 2,2′-biphenols by standard methods10 or
electrochemical protocols fails as a result of the deactivating
(1) (a) Linden, A.; Schaverien, C. J.; Meijboom, N.; Ganter, C.; Orpen,
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(8) Mu¨ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886.
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10.1021/ol101698a  2010 American Chemical Society
Published on Web 08/30/2010

properties of fluoro moieties.11 Only when boron-doped
diamond anodes are employed, less fluorinated 2,2′-biphenols
can be obtained in moderate yields.12 However, substrates
containing more than one fluorine atom show no conversion
in this particular method.13 The common synthetic access
to some derivatives involves the oxidation of lithiated
intermediates.14,15 In several cases the fluorinated biphenols
appear only as byproducts.15,16 The higher fluorinated
biphenols are not reported as prepared compounds but rather
investigated in silico.17
Table 1. Synthesis of Fluorinated Bisanisoles by Ullmann-Type
Coupling
We report a reliable procedure to prepare the highly
fluorinated biphenols by an Ullmann-type coupling reac-
tion.18 As starting material the fluorinated iodo anisoles 2
are used, which are readily accessible by a telescoped
iodination/methylation sequence from commercially available
fluorinated phenols 1.19 The iodination of 1 is carried out
with an I2/I- mixture under alkaline conditions (Scheme 1).20
Scheme 1. Synthesis of the Substrates: Iodination and
O-Methylation of Fluorinated Phenols
Most remarkably, our protocol tolerates bromo substituents
in the Ullmann-type coupling. In previous synthetic studies
bromo derivatives were exploited in the coupling process
itself.3 These brominated biaryls are of specific interest since
they allow further manipulations based on transition metal
cross-coupling reactions.21
For a successful reaction of the iodinated substrates 2,
solvent-free conditions are advantageous, since with the
tested substrates the use of high-boiling solvents as quinoline
or DMPU results in significantly lower yields. Addition of
DMPU tremendously slows down the reaction rate and is
therefore not recommended. However, a well-mixed and
compressed reaction mixture of freshly activated copper and
iodoarenes leads to good and reliable results (Scheme 2).
Scheme 2. Ullmann Coupling of Fluorinated Anisoles
mation. Anisole 2b involves beside the envisioned iodo
leaving group also a bromo moiety, which can act as
functionality for the coupling process. With the elaborated
(11) (a) Scha¨fer, H. J. In Organic Electrochemistry; Bard, A. J.,
Stratmann, M., Eds.; Wiley-VCH, Weinheim, 2004; Vol. 8, p 125. (b)
Yoshida, J.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. ReV. 2008, 108,
2265. (c) Malkowsky, I. M.; Rommel, C. E.; Fro¨hlich, R.; Griesbach, U.;
Pu¨tter, H.; Waldvogel, S. R. Chem.sEur. J. 2006, 12, 7482. (d) Malkowsky,
I. M.; Griesbach, U.; Pu¨tter, H.; Waldvogel, S. R. Eur. J. Org. Chem. 2006,
4569.
Conversion of monofluoro iodoanisole 2a provides the
corresponding bisansiole 3a in a clean reaction with good
isolated yields (Table 1, entry 1). The compatibility of other
halogen substituents was studied in this particular transfor-
Org. Lett., Vol. 12, No. 19, 2010
4289

Scheme 3
.
Byproduct of the Conversion of 2b to 3b in the
Scheme 4. Deprotection of the Fluorinated Bisanisoles
Ullmann-Type Coupling
Table 2. Synthesis of Fluorinated Biphenols by Deprotection of
the Corresponding Bisanisoles with BBr3
conditions the desired bisanisole 3b was obtained in 63%
isolated yield (entry 2).
As a byproduct the 2,2′;4,4′-teranisole 5b was identified
and isolated in 10% yield; 5b is formed by a 2-fold Ullmann
coupling wherein a single bromo function enters the reaction
scene (Scheme 3). However, our conditions tolerate bromo
substituents and still give preparative useful results, despite
the prior use of fluorinated bromoarenes as substrates in the
Ullmann coupling.3 The chloro analogue substrates are less
prone to side reaction and yield the desired biaryls 3c and
3d in good yields (entries 3 and 4). Employment of multiply
fluorinated anisoles as substrates is rendered in significantly
improved yields. Difluoroiodoanisoles 2e and 2f are homo-
coupled in 87% and 95% isolated yield, respectively (entries
5 and 6). An additional fluorine in the substrate leads in the
Ullmann coupling to almost quantitative yields for the
bisanisoles 3g and 3h (entries 7 and 8).
Figure 1. Molecular structure of 3i by X-ray analysis of a single
crystal.
The protocol is not limited to fluorinated 2-iodoanisoles,
since anisole 2i exhibiting the iodo function in position 4 is
successfully converted to the highly functionalized biaryl 3i
(entry 9), although in this case the presence of nitro groups
lowers the yield due to thermal decomposition. For this
reason a slightly lower reaction temperature and a shorter
reaction time is necessary. In order to confirm the aryl-aryl
connectivity, an X-ray analysis of a suitable single crystal
was carried out (Figure 1).
The demethylation reaction is best performed by boron
tribromide (Scheme 4), since strong nucleophiles for the
dealkylation, e.g., sulfide or cyanide, are not compatible with
4290
Org. Lett., Vol. 12, No. 19, 2010

the fluorine moieties on the biaryls. Using excess of the
demethylation agent guarantees quantitative conversions, and
the desired 2,2′-biphenol derivatives 4 are isolated in
excellent yields (Table 2).
While the substrate 3a is demethylated in a short time,
the other bisanisoles require prolonged reaction times. This
might be due to substituents with hetero atoms in the vicinity
of the methoxy functionality. This is also demonstrated in
the conversion of 3f, which is performed much faster since
these heteroatoms are not in the proximity.
Heteroatoms in the positions 6 and 6′ also create a strong
coordinating environment for boron tribromide. Therefore,
reaction of 3h requires larger amounts of reagent and
prolongued reaction time for acceptable yields (Table 2, entry
8). In this case the incomplete conversion after 10 days to
4h was observed and the single deprotected bisanisole could
be isolated in 7% yield. The molecular structure of 4i and
4h was determined by X-ray analysis of suitable single
crystals (Figure 2). A hydrogen bonding pattern was found
only between substituents at the positions 2 and 2′ and not
to the fluorine moieties. A closer look at the packing reveals
a formation of ribbons that are dominated by hydrogen
bonding (Supporting Information).
Figure 2. Molecular structure of 4i (left) and 4h (right) by X-ray
analysis of a single crystals.
biphenols. The required substrates are readily available in
excellent yields by a telescoped iodination/methylation
sequence. The coupling is best performed under solvent-free
reaction conditions. Since iodo groups are the preferred
leaving functionalities, even bromo substituents are tolerated
in this transformation. With an increasing number of fluoro
substituents the coupling process is performed almost
quantitatively. Demethylation to the desired biphenol requires
prolonged reaction times and excess of boron tribromide
since heteroatoms in the vicinity also coordinate to the
reagent and slow down the process. By our approach the
fluorinated 2,2′-biphenols are quickly and reliably prepared.
The application in energy storage devices, e.g., biphenoxy
borates,22 and employment as ligands for catalysis will be
reported in due course.
In conclusion, the Ullmann-type coupling represents the
best synthetic way for the preparation of multiply fluorinated
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Acknowledgment. Financial support by Bundesministe-
rium fu¨r Bildung und Forschung (HE-Lion, 03X4612J) is
highly appreciated.
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Supporting Information Available: Detailed synthetic
procedures and characterization of all products including
crystallograhic data for 3i, 4g, and 4h are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Francke, R.; Schnakenburg, G.; Waldvogel, S. R. Eur. J. Org. Chem.
2010, 2357.
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Ramsden, C. A., Ed.; Thieme: Stuttgart, 2007; Vol. 31, p 235. (b)
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C. A., Thomas, E. J., Eds.; Thieme: Stuttgart, 2010; Vol. 1, p 487.
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