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

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Chapter Four
Further reactions were conducted with (142a) in order to synthesise the methylfluorinated
(R) and (S) analogues of ibuprofen (Figure 4.2). Currently racemic ibuprofen is sold
worldwide, as it converts from the (R) to the (S) isomer after ingestion. The (S) isomer is
called dexibuprofen and has very different pharmacological properties to the racemic
version. Therefore several groups have synthesised chiral derivatives in order to gain
further insight into this system. [19-23] Here, (142a) was converted to (S)- methyl fluorinated
ibuprofen (143) in a similar method to the conventional synthesis of ibuprofen. [24] Firstly,
ozonolysis of (142a) (R and S) was conducted in a methanol/DCM (3:1) mixture at – 78 ºC
for just over 3 hours. Subsequently, reduction with NaBH4 afforded the
monofluoromethylated alcohols in excellent yields and enantioselectivities ((R) = 85 %, 91
% ee, (S) = 87 %, 91 % ee). The sulfonyl group was removed next by reaction with
activated magnesium in methanol at 0 ºC for 2 hours, followed by oxidation with Jones
reagent in acetone at room temperature for 1 hour, to afford the desired product (143) in
good yields with high enantioselectivity, ((R) = 73 %, 91 % ee, (S) = 79 %, 91 % ee).
4.2 Results and Discussion
Figure 4.2 (S)-ibuprofen and (S)-methyl fluorinated ibuprofen
One of the key objectives of this work was to prepare allylic fluorides by reaction of Pd-
allyl species with fluoride ion. Previously, there has only been one, unsuccessful report of
an attempt to achieve this transformation by Togni et al. [25] whereby, initially catalytic
fluorination was attempted with 1,3-diphenylallyl ethyl carbonate, and the catalyst was
generated in situ from Pd(dba)2 and phosphanyl-ferrocenyl pyrazole (Scheme 4.4). The
sources of nucleophilic fluoride tested were TBAT (NBu4[SiF2Ph3]) [26] and Me4NF. [27] Both
are soluble in aprotic organic solvents, thus minimizing any reduction in the nucleophilicity
of fluoride, which can occur by solvation in protic media or in the presence of trace amounts
of water. [28] However, nucleophilic attack of fluoride on the allyl component and the
liberation of an allyl fluoride was never observed. Attempting the reaction with a
stoichiometric amount of palladium was also unsuccessful.