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

17
Chapter One
bromopropiophenone (30) in MeCN at room temperature (Scheme 1.15). The reaction was
followed by gas chromatography and after 38 hours, conversion to 2-fluoropropiophenone
(31) had occurred in a 40 % yield. The reaction was then quenched and the product
isolated, an excess of the (+) enantiomer had formed by kinetic resolution of racemic
starting material.
Scheme 1.15 Asymmetric fluorination of 2-bromopropiophenone by (28)
Enantioselective ring opening of meso- or racemic epoxides by nucleophilic reagents in the
asymmetric synthesis of 1,2-disubstituted compounds has been accomplished with many
different types of nucleophiles. [39] Examples of which are carbon nucleophiles, [40] thiols, [41]
phenols, [42] aromatic amines, [43] azide, [44] cyanide and chloride, bromide or iodide, mediated
or catalysed by different Lewis acids [45] although there had been no reports involving the
use of fluoride. Drawing on evidence from previous studies where it had been observed
that: (i) in order to obtain high enantioselectivity in the ring opening of epoxides an SN2-like
mechanism was desirable, [45] (ii) that Lewis acid activation and nucleophilic attack of the
fluoride equivalent should be concerted or direct delivery of a nucleophile should take place
from a metal centre; (iii) that Jacobsen’s salen complexes were useful catalysts for
enantioselective epoxide ring opening with azides, [46-48] Haufe and Bruns were the first to
report the asymmetric ring opening of meso- and racemic- epoxides by hydrofluorinating
reagents mediated by enantiopure Lewis acidic metal complexes. [49] Cyclohexene oxide
(32) was reacted with KHF2/18-crown-6 and 100 mol% of (S,S)-(+)-(salen)chromium
chloride complex in DMF at 60 ºC (Scheme 1.16). After 80 hours, 92 % of the epoxides
had been consumed, yielding (R,R)-(-)-2-fluorocyclohexanol (33) (55 % ee) and (R,R)-(-)-2-
chlorocyclohexanol (34) (20 % ee) in the crude product mixture. The reaction was repeated
with only 10 mol % of (S,S)-(+)-(salen)chromium chloride complex, however, the reaction
temperature had to be increased to 100 ºC which caused the enantioselectivities to drop,
with products (33) and (34) formed in a 94:6 ratio but (33) showing only 11 % ee. The
formation of the chlorohydrin may be due to partial transfer of chloride directly from the
complex to the epoxide (SN2 reaction).