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

24
Chapter One
Manabe and Ishikawa [74] reported the first examples of ortho-selective cross-coupling
reactions of fluorobenzene bearing electron-donating groups. After screening several Pd
catalysts, dichlorobis(tricyclohexylphosphine) palladium [PdCl2(PCy3)2] was found to be
the most effective and was utilised in reactions with chlorofluorophenol, difluorophenols
and fluorobenzenes bearing hydroxymethyls and amino groups, affording the corresponding
products in good to excellent yields (49-85 %). The reaction protocol was also extended to
fluorophenylmagnesium bromide with fluorophenol and difluorophenol both affording the
corresponding product in excellent yields (74-85%).
Scheme 1.23 Ortho-selective cross-coupling reactions of fluorobenzene
Though electrophilic reagents are most commonly used for the substitution chemistry on
aromatic rings, replacement of a fluorine atom can also be conducted with nucleophiles by
either nucleophilic substitution or transition metal catalysed coupling with organometallics.
This was demonstrated by Robertson [75] where (S)-3-(methylamino)-1-phenylpropanol was
reacted with NaH in dimethylacetamide (DMAC) in order to generate the alkoxide, and
subsequent addition of 4-fluorobenzotrifluoride led to nucleophilic aromatic substitution,
affording the desired (S)-fluoxetine, an anti-depressant of the selective serotopin reuptake
inhibitor.
Scheme 1.24 Synthesis of (S)-fluoxetine
Quinoline carboxylic acid derivatives are useful antibacterial agents which can be
synthesised by the regioselective nucleophilic displacement of polyfluorinated arenes. This