DOI: 10.1002/chem.201405119
Communication
&
Synthetic Methods
Pd- and Cu-Catalyzed Stereo- and Regiocontrolled
Decarboxylative/CÀH Fluoroalkenylation of Heteroarenes
Kevin Rousꢀe, Cꢀdric Schneider, Samuel Couve-Bonnaire,* Xavier Pannecoucke,
Vincent Levacher, and Christophe Hoarau*[a]
Abstract: Pd/Cu-catalyzed decarboxylative/direct CÀH al-
kenylations of heteroarenes with a-fluoroacrylic acid is re-
ported. This method offers step-economical and stereo-
controlled access to valuable heteroarylated monofluor-
oalkenes as both Z and E isomers, which are known to be
useful in the synthesis of fluorinated biomolecules.
Transition metal-catalyzed CÀC bond formation through direct
CÀH functionalization of heterocycles has proven to be an effi-
cient modern alternative and complementary process to tradi-
tional cross-coupling methods.[1] Within the direct functionali-
zation of ubiquitous CÀH bonds, direct alkenylation,[2] an
emerging tool for the construction of alkenylated (hetero)ar-
enes, has recently received growing attention due to the sig-
nificance of this motif in biologically active natural products,
pharmaceuticals and organic materials.[3]
In recent years, current developments in the transition
metal-catalyzed direct CÀH alkenylation of heteroaromatics
have been mainly focused on: (1) the Fujiwara-Moritani oxida-
tive Heck-type coupling with simple alkenes,[4] (2) the hydroar-
ylation of alkynes,[5] and (3) the direct CÀH alkenylation with al-
kenyl halides or pseudohalides, more valuable coupling part-
ners than alkenes or alkynes for controlling both the regio-
and stereochemistry of this process.[6] Although prefunctional-
ized halo- or pseudohaloalkenes have been widely investigated
[Scheme 1, Equations (1) and (2)], we turn our attention to the
attractive acrylic acid derivatives due to their ready availability
and easy access to both substituted E and Z isomers. Recently,
the groups of Itami and Xu/Li have reported the first nickel
and rhodium-catalyzed decarbonylative/CÀH alkenylations of
(hetero)arenes using acrylates as alkenylating reagent
[Scheme 1, Equation (3)].[7] Herein, we report the first investiga-
tion of decarboxylative CÀH alkenylation of heterocycles with
acrylic acids [Scheme 1, Equation (4)], through a conventional
catalytic cross-coupling process that combines the generation
of an alkenylcopper intermediate as a transmetallating agent
Scheme 1. Previous [(1)–(3)] and proposed [(4)] methodologies for direct CÀ
H alkenylations of heterocycles using prefunctionalized alkenes.
by copper-catalyzed extrusion of CO2 with the catalytic CÀH
palladation of the heterocycle (Scheme 1).[8–11]
a-Fluoroacrylic acid has been especially selected to address
important challenges in catalytic decarboxylative cross-cou-
pling chemistry, as well as in the attractive field of fluorinated
biomolecules.[12] This choice originated indeed, from the fol-
lowing premises: 1) To establish a first proof of concept of
direct CÀH/CÀCO2H cross-coupling between heterocycles and
acrylic acids, we anticipated that a-fluoroacrylic acids would
be excellent candidates due to the electron-withdrawing effect
of the fluorine atom that may facilitate the ipso-decarboxyla-
tive metallation process;[13] 2) Our recent successful use of
gem-bromofluoroalkenes as efficient coupling partners in Pd-
catalyzed direct CÀH alkenylation of heteroarenes [Scheme 1,
Equation (2)] demonstrating that fluoroalkenes are stable
under such catalysis compared to their gem-dibromo-
(dichloro)alkene counterparts leading to alkynylated prod-
ucts;[14] 3) importantly, the monofluoroalkenes[15] are highly val-
uable organic compounds, which have found many applica-
tions as, for example, materials,[16] drugs,[17] and peptidomimet-
ics.[18] Herein, we report the first decarboxylative/CÀH alkenyla-
tion of heterocycles with various (E)- and (Z)-a-fluoroacrylic
acids offering an innovative step-economical, eco-friendly and
[a] K. Rousꢀe, Dr. C. Schneider, Dr. S. Couve-Bonnaire, Prof. X. Pannecoucke,
Dr. V. Levacher, Prof. C. Hoarau
Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen;
CNRS, IRCOF, 1 rue Tesniꢁre 76821 Mont-Saint-Aignan Cedex (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405119.
Chem. Eur. J. 2014, 20, 15000 – 15004
15000
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim