DOI: 10.1002/chem.201500551
Communication
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Fluoroalkylation
Pd-Catalyzed Difluoromethylation of Vinyl Bromides, Triflates,
Tosylates, and Nonaflates
Dalu Chang, Yang Gu, and Qilong Shen*[a]
tion of difluoromethylated alkenes have been much less ex-
Abstract: Pd-catalyzed difluoromethylation of di-, tri- or
plored. Only recently, the groups of Hartwig and Surya Prakash
tetra-substituted vinyl bromides, triflates, tosylates and
have reported copper(I)-mediated reactions of vinyl iodides
nonaflates under mild conditions is described. The reac-
with nucleophilic difluoromethylated reagents.[8c,d] However, re-
tion tolerates a wide range of functional groups, such as
actions with easily available vinyl sulfates, such as triflates,
bromide, chloride, fluoride, ester, amine, nitrile, and pro-
nonaflates, and tosylates, have not been reported. Liu and co-
tected carbonyl, thus providing a general route for the
workers reported an iron-catalyzed decarboxylative difluoro-
preparation of difluoromethylated alkenes.
methylation of electron-rich aryl-substituted acrylic acids with
moderate yields under mild conditions.[10] However, electron-
deficient aryl-substituted acrylic acids gave very low yields
The beneficial “fluorine effect” on drug molecules has been
well recognized in the field of medicinal and agro-chemistry, as
evidenced by the growing number of fluorinated drugs and
agrochemicals on the market and drug candidates at develop-
mental stages.[1] Typically, most of these molecules contain
a fluorine or a trifluoromethyl group.[2] In comparison, com-
pounds bearing a difluoromethyl group (-CF2H) have been
much less prominently marketed.[3] Nevertheless, interest in
this structural unit is growing rapidly, since the difluoromethyl
group is known to be a bioisostere of carbinol or thiol groups
in drug design.[4] In addition, the difluoromethyl group can act
as a lipophilic hydrogen bond donor that could improve the
molecule’s binding selectivity and cell membrane permeability.
Consequently, these interests in the medicinal chemistry com-
munity have stimulated many research groups to develop effi-
cient methods for the incorporation of the difluoromethyl
group into organic molecules under mild conditions.[5] In the
past five years, several elegant methods for the construction of
difluoromethylated arenes or heteroarenes have been achieved
either through radical-based fluorination[6] and difluoromethy-
lation[7] processes, or through transition metal-catalyzed direct
difluoromethylation of aryl halides or diazonium salts.[8]
under the same reactions conditions. Thus, efficient methods
for the introduction of difluoromethyl onto alkenes are highly
desirable.[11]
As a part of ongoing efforts on the development of efficient
methods for late-stage introduction of fluoroalkyl groups into
small molecules through transition metal catalysis,[12] we report
herein the first example of palladium-catalyzed direct difluoro-
methylation of di-, tri-, or tetra-substituted vinyl bromides, tri-
flates, tosylates, and nonaflates under mild reaction conditions,
thus providing a general solution for the high efficient synthe-
sis of a wide range of functionalized difluoromethylated al-
kenes.
We recently reported a cooperative bimetallic Pd/Ag-cata-
lyzed difluoromethylation of aryl bromides and iodides using
TMSCF2H as the difluoromethyl source and NaOtBu as the acti-
vator.[8j] We envisaged that, under similar conditions, the palla-
dium-catalyzed difluoromethylation of alkenyl electrophiles
might provide a straightforward solution. However, use of
a palladium catalyst for the formation of difluoromethylated al-
kenes is a challenging task, since, in the presence of a palladi-
um catalyst, the allylic CÀF bond in difluoromethylated alkenes
has been known to undergo an irreversible oxidative addition,
and subsequent further transformation will give defluorinated
compounds.[13] For example, Gouverneur and co-workers re-
ported that palladium-catalyzed allylic alkylation of monoallylic
fluoride occurred at room temperature, whereby a CÀF bond is
replaced by a CÀC bond.[14a] Paquin and co-workers reported
that, under palladium-catalyzed conditions, one of the CÀF
bonds in 3,3-difluoropropenes could be activated and func-
tionalized at slightly increased temperature (708C).[14b] Thus,
a highly activated palladium catalyst is needed that could pro-
mote reductive elimination from a [L2Pd(vinyl)(CF2H)] complex
to form the difluoromethylated alkene, while, at the same
time, prohibiting the allylic CÀF bond activation process
(Scheme 1).
Owing to their similar steric and electronic properties, fluo-
roalkylated alkenes are generally considered to be capable of
replacing a peptide bond in peptidomimetics to improve bio-
logical activity.[9] Hence, difluoromethylated alkenes could act
as a very useful structural component in drug design. In spite
of remarkable progress in the development of new methods
for difluoromethylation of arenes, protocols for the construc-
[a] D. Chang, Y. Gu, Prof. Dr. Q. Shen
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P. R. China)
With these thoughts in mind, we initially studied the palladi-
um-catalyzed coupling of b-bromostyrene with trimethylsilyldi-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500551.
Chem. Eur. J. 2015, 21, 1 – 6
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chang, Dalu
