Angewandte
Chemie
DOI: 10.1002/anie.201408812
Hypervalent Compounds
Mild Silver-Mediated Geminal Difluorination of Styrenes using an Air-
and Moisture-Stable Fluoroiodane Reagent**
Nadia O. Ilchenko, Boris O. A. Tasch, and Kꢀlmꢀn J. Szabꢁ*
Abstract: An air- and moisture-stable fluoroiodane in the
ologies are usually based on metal-catalyzed cross-coupling of
presence of AgBF is suitable for selective geminal difluorina-
various CF carriers with aryl halides and boronates. For
4
2
[
11]
[12]
tion of styrenes under mild reaction conditions. One of the CÀF
bonds is formed by transfer of electrophilic fluorine from the
hypervalent iodine reagent, while the other one arises from the
tetrafluoroborate counterion of silver. Deuterium-isotope-
labelling experiments and rearrangement of methyl styrene
substrates suggest that the reaction proceeds through a pheno-
nium ion intermediate.
example the groups of Amii,
Hartwig,
Prakash and
[
13]
[14]
Olah, and Qing used a copper catalyst (or mediator),
[15]
while the group of Zhang used palladium catalysis for the
introduction of a CF group to organic substrates. Baran and
2
co-workers have published a series of papers on CÀH
[
16]
difluoromethylation by CF H radicals. Introduction of the
2
difluoromethyl group with consecutive difluorination reac-
tions is a less common approach compared to the above-
O
rganofluorines are very important substances in pharma-
mentioned cross-coupling of CF units with the organic
2
[
17]
ceutical and agrochemical industries and have also had an
substrate. Tang and co-workers have shown that consec-
utive geminal difluorination of aromatic benzyl groups can be
achieved by using Selectfluor as a fluorine source in
combination with a silver catalyst under oxidative conditions.
A similar reaction has been reported by Chen and co-
[
1]
increasing role in medicinal research and diagnostics. As
organofluorine compounds are specific regulator substances,
inhibitors, or biomarkers, constant development of new
methodologies for their selective synthesis is a very important
task in synthetic chemistry. The appearance of new stable,
electrophilic fluorinating reagents and methodologies
allowed the extension of the new methodologies for selective
[18]
workers
using visible-light-promoted reactions under
metal-free conditions. For both reactions a radical mechanism
was postulated.
[
2]
synthesis of a large variety of organofluorine compounds. In
Recently, development of new fluorination reactions by
application of hypervalent iodine reagents has attracted
recent years creation of single CÀF bonds, introduction of
[
2a,b,19]
CF , and trifluoromethylation reactions have received a lot of
considerable attention.
fluorochemistry program,
As a part of our synthetic
2
[
20]
attention. Of these major areas the introduction of a CF
group is probably the least developed. Nevertheless, the
difluoromethyl group proved to be an important motif in
enzyme inhibitors. This property is probably a result of the
ability of the CF H group to donate hydrogen bonds, and,
we have studied the potential
2
[
3]
[19f,21]
use of the hypervalent fluoroiodane 1
as an electrophilic
organofluorinating reagent [see Eq. (1)]. The fluoroiodane
[
4]
1 is an air- and moisture-stable crystalline compound and
[
5]
[2a,22]
structural analogue of the Togni reagent,
which has been
2
[6]
thus serve as a bioisoster for hydroxy and thiol moieties.
one of the most successful electrophilic trifluoromethylating
reagents in organic synthesis. Another attractive property is
that 1 can be obtained from its chloro analogue by addition of
Furthermore, very recently CF2 groups have found new
applications in medicinal diagnostics as well. A new trend in
the synthesis of trifluoromethyl-group-based PET tracers is
substitution of suitable sp difluoromethyl groups with F to
obtain FCF functionalities.
The early methods for introducing difluoromethyl groups
to organic molecules were mainly based on the application of
highly reactive inorganic fluorinating reagents, such as
[21b]
KF.
Thus, synthesis of 1 using KF involves a simple
3
18
umpolung method by changing a nucleophilic fluorine into an
electrophilic one. This simple possibility for umpolung of the
fluorine atom can be a useful feature for the development of
1
8
[7]
2
[23]
new tracers for medicinal diagnostics. The first report by
[
21a]
Legault and Prꢀvost
on the attempts to use 1 for CÀF
[8]
[9]
[10]
DAST, Deoxofluor, and XeF2.
However, application
bond-formation reactions was disappointing. In contrast to its
bromo analogue, 1 was not suitable for the electrophilic
halogenation of anisole. According to Stuart and co-work-
of these reagents may lead to problems in functional-group
tolerance and selectivity, and causes hazardous HF develop-
ment upon contact with water. The recently reported method-
[19f]
ers
1 reacts with 1,3-diketoesters and 1,3-diketones in the
presence of TREAT-HF to give mono- and difluoro products,
respectively. As far as we know, this paper by Stuart and co-
[
*] N. O. Ilchenko, Dr. B. O. A. Tasch, Prof. K. J. Szabꢀ
Department of Organic Chemistry, Stockholm University
E-mail: kalman@organ.su.se
[19f]
workers
has been the only report on the application of
1
for creating CÀF bonds.
We have now found [Eq. (1)] that mixing of equimolar
Homepage: http://www.organ.su.se/ks/
amounts of the styrene 2a, 1, and AgBF (3) results in the
4
[
**] Support by the Swedish Research Council and the Knut and Alice
Wallenbergs Foundation, as well as a post-doctoral fellowship for B.
O. A. T. by the Tryggers foundation is gratefully acknowledged.
difluoro compound 4a under mild reaction conditions (408C).
The reaction was very clean and the yield of the isolated
product was over 50%, thus indicating that in the geminally
difluorinated product one of the fluorine atoms was derived
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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