Synthesis and Comparison of the Reactivity of Allyl Fluorides and ...

1.5 C-F Activation
23
Chapter One
Carbon-fluorine bond activation though less explored than carbon-fluorine bond formation
is invaluable, especially in the synthesis of partially fluorinated compounds which would be
otherwise inaccessible or more difficult to prepare.
1.5.1 Aromatic Fluorides
The cross-coupling reaction with selective C-F activation of polyfluoroarenes is a useful
tool for the synthesis of partially fluorinated aromatics. Recent work by Saeki et al. [73] has
examined the cross-coupling reaction of 1,2-, 1,3- and 1,4-difluorobenzenes with p-tolyl
magnesium bromide. Initially the optimised reaction conditions from the reaction of
monofluorobenzene were used ([NiCl2(dppp)] (0.01 equivalents) p-tolylmagnesium bromide
(1.5 equivalents)), however, this afforded a mixture of both the mono-coupled and di-
coupled products, whilst increasing the amount of Ni catalyst and p-tolylmagnesium
bromide simply increased formation of the undesired di-coupled product. Therefore, the
catalyst was replaced by [PdCl2(dppf)], which was found to be far more effective, with
formation of the mono-coupled product exclusively in 91 % yield. However, this was only
in the case of 1,2-difluorobenzene. With 1,3 and 1,4-difluorobenzene, although only the
mono-coupled products were formed, the yields obtained were substantially lower 15 % and
6 % respectively (Scheme 1.22). Therefore, it was proposed that the chelating effect of the
adjacent fluorine atom in 1,2-difluorobenzene was integral in promoting the oxidative
addition of the fluorine bond. Extension of this protocol was also applied to
trifluorobenzenes where it was found that [PdCl2(PPh3)2] and [PdCl2(dppf)] were better at
yielding the desired mono-coupled product than [NiCl2(dppp)]. With 1,2,3-trifluoro
benzene, the Pd catalysed reaction afforded the corresponding mono-coupled product in
69 % yield, whilst with the Ni catalyst 41 % of the di-coupled product was afforded, with
none of the mono-coupled one. A similar scenario was observed with 2,4,6-
trifluorobenzene, where the Pd catalysed reaction afforded the desired mono-coupled
product in 60 % yield whilst the Ni catalyst afforded 60 % of the tri-coupled product.
Scheme 1.22 Cross-coupling reaction of 1,2-, 1,3- & 1,4-difluorobenzenes with p-tolylMgBr