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

115
Chapter Five
on attack of the chlorine atom of the chlorodifluoromethyl ketone, yielded the
corresponding enolate. [11] Following on from this work, Ishihara and Kuroboshi found that
the use of copper chloride [18, 19] or silver acetate as catalysts also improved the reaction of
chlorodifluoromethyl ketones with carbonyl compounds to yield the corresponding ���-
difluoro-�-hydroxy ketones in high yields (60-100 %). Further studies by Lang
demonstrated that inexpensive chlorodifluoroacetic acid was a viable replacement for
bromodifluoroacetic acid, with higher yields afforded when the reaction was conducted in
DMF. [20] Whilst milder conditions could be employed by using a catalytic amount of
CeCl3 [21] or Et2AlCl with AgOAc. [22] Altenburger reported how the use of ultrasonication at
room temperature under inert conditions enabled the generation of the organozinc reagent
prior to the addition of the aldehyde. This is especially essential when using nitro
aldehydes, where a two-step process is required, as the traditional one-pot reflux procedure
results in 0 % yield, in contrast to 80 % yield of product when ultrasonication was
employed. [23]
Yamana [24] reported the first synthesis of 2,2-difluoro enol silyl ethers from chloro
difluoromethyl ketones by reaction with zinc dust and chlorotrimethylsilane in anhydrous
acetonitrile at 60 ºC. Yields obtained varied from moderate to good (35-74 %). However,
Kitagawa found that though silyl enolates generated from halodifluoroketones could be
isolated, those generated from halodifluoroesters [25] were found to be unstable and
subsequently were reacted in situ with the zinc dihalide acting as a Lewis acid. The use of
silylenol ethers as intermediates was found to improve the stereoselectivity of the reaction.
Generally, Reformatsky reactions preferentially yield the syn product with �-alkyloximes
and �-aminoaldehydes and the anti product with �-hydroxyaldehydes (Scheme 5.2).
Scheme 5.2 General reactions of silyl enolates