Chemistry Reference
In-Depth Information
stage, the organic solvent elutes the products and the
fluorous eluent contains the fluorous molecule,
which usually can be recovered for further tagging
processes.
The strategy of fluorous labelling was demon-
strated through the parallel synthesis of a small
isoxazoline library, as an alternative to solid-phase
combinatorial chemistry (Fig. 22.18) [61,111].
The selected labelling reagent for this application
was a highly fluorinated bromosilane derivative
(R
f
6
CH
2
CH
2
)
3
SiBr that contained three perfluoro-
hexylethyl units, similar to the previously described
tin reagent. Allyl alcohols were rendered fluorous
upon attachment to this label in typical silylation
reactions (Fig. 22.18, 1. labelling). The cycloaddition
reactions of these fluorinated allyl derivatives with
in-situ-generated nitrile oxide, following standard
Huisgen or Mukaiyama procedures, were performed
under homogeneous reaction conditions in CH
2
Cl
2
or
BTF solvent (Fig. 22.18, 2. reaction). The fluorous
isoxazoline compounds were obtained in high yields
and purities, which could allow further reaction
steps, if desired, for other automated synthesis pur-
poses. The fluorosilyl tags were removed from the
cycloadducts under mild conditions with HF-
pyridine reagent in diethyl ether (Fig. 22.18, 3.
detachment). At all stages of the reaction, the com-
ponents were separated by simple three-phase
liquid-liquid extractions (fluorous: FC-72/organic:
CH
2
Cl
2
or benzene/aqueous).
The suitability of fluorous phase labelling methods
for combinatorial synthesis of organic molecules
with pharmaceutical potential was evaluated for Ugi-
and Biginelli-type multicomponent condensations
[112]. Because the technical development of these
two reactions is very similar, here we consider only
the Ugi-type four-component condensation (Fig.
22.19). The labelling is based on silane chemistry, as
Fig. 22.16
Fluorous thermal allylation reaction using extractive
and chromatographic work-up.
In a control experiment it was shown that a normal
C
18
reverse silica gel could not separate efficiently the
fluorinated and non-fluorinated components, indi-
cating an important role of fluorine-fluorine inter-
actions between the FRP silica support and the
fluorous compounds.
8 Fluorous Tags
The temporary attachment of highly fluorinated
units to different substrates, introduced also by
Curran, opens large perspectives in the field of
separation techniques in organic synthesis [111].
Owing to the role of the so-called 'fluorous tags'
applied at appropriate stages of the reaction, a
number of novel fluorous techniques have been
introduced [61,82,112,113], such as the application
of fluorous phase labels in multistep syntheses—the
name 'fluorous synthesis' referred originally to this
method, and the meaning of the concept was
extended to all fluorous techniques only later
[100]—or fluorous phase switches (or scavengers)
(Fig. 22.17).
The key idea of all these tagging procedures is that
the connection of a highly fluorinated module
renders selectively one component (or one class of
components in the case of parallel synthesis) fluor-
ous soluble, leading to facile separation from other
organic and inorganic components by simple extrac-
tive work-up, or by fluorous reverse-phase chro-
matography. At a later point of the synthesis or
purification, the fluorous tag is cleaved and the
product can be extracted to the organic phase while
the fluorous compound remains in the fluorous
liquid. When FRP chromatography is used at this
