G Model
FLUOR-8584; No. of Pages 4
Journal of Fluorine Chemistry
Simple and expedient metal-free C–H-functionalization of
fluoro-arenes by the BHAS method – Scope and limitations
Stephanie Lindner a,1, Stefan Bra¨se a,b, , Kye-Simeon Masters
*
c,**
a Karlsruhe Institute of Technology (KIT), Institute of Organic Chemistry, Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany
b Institute of Toxicology and Genetics, Hermann-von-Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany
c Chemistry, Physics and Mechanical Engineering School (CPME), Queensland University of Technology (QUT), PO Box 2434, 2 George Street, Brisbane, 4000
QLD, Australia
A R T I C L E I N F O
A B S T R A C T
Article history:
We report here the facile substitution of aromatic iodides with non-activated fluoroarenes through
radical-promoted reaction conditions. Applying the recently-popularized BHAS methodology, catalytic
1,10-phenanthroline and KOtBu and the desired fluorobenzene as reactant and solvent, various
fluorinated biaryls can be synthesized in moderate to good yields. The method provides a simple access
Received 16 April 2015
Received in revised form 9 June 2015
Accepted 10 June 2015
Available online xxx
to generate potentially many ‘FnAr’-substituted derivatives from
a single haloarene synthetic
intermediate, using relatively cheap and non-toxic fluoroarene substrates directly from the bottle,
and may therefore be of use for medicinal chemistry campaigns. Although the method has a limitation in
that it is not compatible with substrates featuring base-sensitive substituents, especially 1,4-
difluorobiaryls are accessible in good yields. These investigations facilitate the exploitation of the
potential of this protocol to synthesize biologically active fluorinated biaryls, e.g. WNT-active molecules.
ß 2015 Published by Elsevier B.V.
Keywords:
Aromatic
BHAS
Radical
1. Introduction
In the latter context, metal-catalyzed reactions in particular
with the aid of copper [25–27], palladium [28,29], platinum [30]
Fluorinated arenes play a pivotal role in pharmacological
applications and material sciences. In particular fluorinated biaryls
have shown activity in many different biological systems. Notable
examples are the drug diflunisal [1–11], the fungicide fluxapyr-
oxad [12] or the WNT-active molecules 3 and 4 [13,14], shown in
Fig. 1.
So far, around 70,000 fluorinated, 45,000 difluorinated and
20,000 trifluorinated biaryls have been reported (according to
Scifinder). Besides the classical cross-coupling Suzuki, Stille,
Kumada and Ullmann reactions [15] (for references from our
labs: [16–19]) (Scheme 1, left), arylation by classical aryl radicals
generated from peroxides [20] or other sources like diazonium
salts [21], or dimerization reactions [22], selective C–H activation
reactions of fluorinated arenes emerged recently (Scheme 1, right)
(for references from our labs: [23,24]).
complexes or with aluminum [31] (for a comparison: [32]) have
been used very successfully.
Recently the H-substituting arylation of simple arenes with
haloarenes has been shown to proceed in the absence of transition
metals. This method, the Base-Promoted Homolytic Aromatic
Substitution (BHAS) is a new base-driven form of the long-known
homolytic aromatic substitution [33]. The reaction requires excess
alkali-metal tertiary-butoxide base (usually KOtBu) alongside an
activating additive with chelating heteroatoms, usually phenan-
throline [34], or related heterocycles like pyridines [35] or
quinolones [36], alternatively phenylhydrazine, porphyrins and
even amino acids like proline [37].
The BHAS reaction has been used for the synthesis of fluoro-
decorated biaryls on occasion. It should be noted that these
examples are scarce and a broad investigation of the scope was still
required.
During our exploration of the acetal method for the construc-
tion of dibenzo[1,3]dioxepines, 2,20-biphenols and biaryls more
generally [23,24], we found that substrates designed to provide
cyclization/coupling cascade reactions can allow the incorporation
of a wide range of arenes, including 1,4-difluorobenzene [38]. This
finding prompted us to investigate the intermolecular arylation of
(poly)fluoroarenes with functionalized arenes.
*
Corresponding author at: Karlsruhe Institute of Technology (KIT), Institute of
Organic Chemistry, Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany.
Tel.: +49 721 608 4 2902.
**
Corresponding author. Tel.: +61 414 455 181.
(K.-S. Masters).
1
Tel.: +49 721 608 4 2902.
0022-1139/ß 2015 Published by Elsevier B.V.