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

7
Chapter One
The first N-fluorosulfonamide synthesised by Takeuchi and Shibata was N-fluoro-3-
cyclohexyl-3-methyl-2,3-dihydrobenzo[1,2-d]-isothiazole-1,1-dioxide (CMIT-F) (8). [21]
This was prepared in five steps, with fluorination in the final step proceeding via 15 %
F2/He affording the product in a 65 % yield. CMIT-F (8) was reacted with various ketones
to evaluate its enantioselective fluorinating ability, with reactions carried out using 1.1-1.3
equivalents of LDA and 1.1-1.3 equivalents of fluorinating agent in THF solution. The
optimal result was obtained with 2-benzyl-1-tetralone, which yielded the fluorinated product
in 79 % and 88 % ee. However, all other enantioselectivities were moderate ranging from
18-74 %.
After developing CMIT-F (8) it was evident that the enantioselectivity of the fluorination
reaction was dependent on the difference in steric bulk of the two substituents at the chiral
centre. Therefore, N-fluoro sultam (11) was synthesised, however, under reaction conditions
with lithium enolates the corresponding imine was formed (12). This was attributed to the
acidity of the proton at the chiral centre which leads to HF elimination. (R)- and (S)-N-
fluoro-3-tert-butyl-7-nitro-3,4-dihydro-2H-benzo[e][1,2]-thiazine-1,1-dioxides (BNBT-F)
(9), were designed with the proton at the chiral centre to be significantly less acidic, but
with the differential bulk of the two substituents at the chiral centre to be sufficient to
induce high enantioselection (Figure 1.6). The electron-withdrawing nitro group was
introduced into the aromatic ring to increase the fluorinating ability of the reagent. [22]
Figure 1.6 The structures of (BNBT-F) (9), (11) and (12)
The two enantiomers of BNBT-F (9) were prepared in three steps, with fluorination in the
final step proceeding with FClO3 in THF to afford (R) and (S)-(9) in 66 % and 83 % yields
respectively. Once synthesised their fluorinating ability was tested with a series of
tetralones and indanones. Enantioselectivities were moderate to high, ranging from 42-69
%.
The third N-fluorosulfonamide, synthesised by Takeuchi and Shibata, was 2-fluoro-14-
methyl-11-(methylethyl)-spiro[4H-benzo[e]-1,2-thiazine-3,2’-cyclohexane]-1,1-dione (10),