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

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Chapter Five
The first enantioselective Reformatsky reaction was reported in 1995 by Braun.
Benzaldehyde was reacted with methyl bromodifluoroacetate in the presence of chiral-�-
amino alcohols, affording the desired product in 61 % yield and 84 % ee. [26]
The versatility of Reformatsky reactions has enabled its use to form general synthons for
further functionalisation, [27, 28] in addition to the preparation of difluoromethylene analogues
of amino acids for the incorporation into peptides. [29] Two significant examples being
potent HIV protease inhibitors [30] and renin inhibitors [31] both prepared under standard
unactivated conditions.
5.1.2 Difluoroallyl anions
Difluoroallyl anions are versatile synthons for the synthesis of gem-difluorinated molecules.
In 1979 Seyferth [32] reported the synthesis of difluoroallyllithium by transmetallation of
gem-difluoroallyl stannane with n-butyl lithium. However, it was found to be unstable in
solution even at -95 ºC (Scheme 5.3).
Scheme 5.3 Synthesis of difluoroallyllithium
Therefore, 3-bromo-3,3-difluoropropene was utilised as an alternate precursor of gem
(difluoroallyl) lithium. It was postulated that the CH2=CHCF2Br/n-BuLi reaction would
proceed at a rate comparable to or even faster than the addition of n-BuLi to the carbonyl
substrate when an in situ procedure is used. The CH2=CHCF2Br/n-BuLi reaction was
conducted in a 5:1:1 mixture of THF/Et2O/pentane at -95 ºC under a nitrogen atmosphere in
the presence of an excess of triorganosilane with good yields of the desired
R3SiCF2CH=CH2 obtained (27-74 %). Whereas previously with Me3SnCH2CH=CF2/n-
BuLi, the difluoroallyl lithium was generated by reaction at the CH2 terminus, in
CH2=CHCF2Br/n-BuLi difluoroallyl lithium is generated by reaction at the CF2 terminus
(Scheme 5.4). However, in both cases the same intermediate is formed.