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

5.1 Introduction
5 Synthesis and Reactions of Difluoroallylic Compounds
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Chapter Five
The CF2 group is a key structural unit in many fluorinated compounds of biological and
pharmaceutical significance. [1] The synthesis of gem-difluorinated compounds can be
conducted in two ways either by direct fluorination, which can occur by the use of
nucleophilic [2-6] or electrophilic [7-9] fluorinating agents, or by utilising a difluoro building
block. [10, 11] This chapter will focus on the latter approach in order to synthesise an
analogous library of allylic difluorides to the allylic fluorides and chlorides synthesised in
Chapter Two. Once synthesised the allylic difluorides will be utilised in reactions with
Pd(0), as although allylic fluorides can be activated with Pd, in doing so they lose fluorine
and react with nucleophiles to afford non-fluorinated products. However, activation of
allylic difluorides followed by reaction with nucleophiles would yield fluoroalkenes. These
products are an important class of compounds that can be utilised as peptide isosteres, [12-15]
enzyme inhibitors [16] and in liquid crystalline materials. [17]
5.1.1 Difluoromethylene Synthons
The most common CF2 synthon approach is the Reformatsky reaction of
halodifluoroacetates and halodifluoroketones. Fried reported the preparation of 2,2-
difluoro-3-hydroxy esters by the Reformatsky reaction of ethyl bromodifluoroacetate with
aldehydes and ketones in 1984 (Scheme 5.1). [10] Upon comparison of both the one pot and
2-step procedure, Fried found that addition of the aldehyde after the zinc had reacted with
ethyl bromodifluoroacetate for a few minutes led to higher yields of product and was,
therefore, preferred. It could also be used for the synthesis of more sensitive substrates as it
required lower reaction temperatures.
Scheme 5.1 General reaction scheme for the synthesis of 2,2-difluoro-3-hydroxyesters
Simultaneously, Ishihara reported the zinc-mediated reaction of chlorodifluoromethyl
ketones with aldehydes and ketones affording 2,2-difluoro-3-hydroxy ketones in moderate
to good yields (38-95 %). It was found that a catalytic quantity of titanium tetrachloride
was integral to the reaction, as with zinc alone only starting material was afforded.
Therefore, the reactive species in the reaction was the bivalent titanium compound which,