Technology Note
Visual Monitoring of Solid-Phase Extraction Using Chromogenic
Fluorous Synthesis Supports
Christopher Blackburn*
Discovery, Millennium Pharmaceuticals Inc., 40 Landsdowne Street, Cambridge Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: Reductive aminations and further transforma-
tions of an azo dye and fluorous tagged aldehyde are described.
The intensely colored 2,4-dialkoxybenzyl protected amines
undergo Fmoc-based peptide coupling, Suzuki reactions, and
sulfonamide formation with product isolation facilitated by
visual monitoring of fluorous solid phase extraction. Target
compounds are released from the supports in high yields and
purities by treatment with trifluoroacetic acid (TFA).
KEYWORDS: fluorous, synthesis support, azo dye, solid-phase extraction
ince its introduction by Curran and co-workers,1 light
monitored, instantaneously, using a colored fluorous tag. Thus,
Sfluorous tagging (usually defined as a single tag with
in a manual or automated fluorous facilitated synthesis the
no more than 21 fluorine atoms) of reagents and substrates
coupled with fluorous solid-phase extraction (F-SPE)2 has become
a valuable component of solution phase parallel synthesis.3 The
technique takes advantage of the selective interactions between
highly fluorinated molecules to effect partitioning of the fluorous
tagged components into the fluorous stationary phase leading to
rapid isolation and purification without the need for laborious
conventional extraction and chromatography procedures. In cases
where the substrate carries the fluorous tag, reaction mixtures are
applied to fluorous silica gel cartridges and the unretained
byproduct diverted to waste. The desired fluorous tagged product
is then eluted from the cartridge using a fluorophilic solvent and
advanced to the next step in the synthesis. Ideally, the SPE process
(as distinct from chromatography) affords only one fraction for
collection and analysis, and detailed experimental procedures have
been published describing loading capacities, optimal flow rates,
solvent compatibilities, and eluent strength.4 Optimization of the
elution step may be required, however, to prevent leaving
compound behind on the cartridge because of low solubilities
or, in the case of basic molecules, adsorption at uncapped silanol
residues of the base silica gel.5 Moreover, solubilities and basicities
may not be uniform across the members of a parallel synthesis
library and, when using conventional tags, it is only after
evaporation and gravimetric analysis that product recoveries are
determined. Retaining cartridges for further elution and waste
tubes to guard against losses in the loading and first pass elution
steps can be inconvenient especially when processing multiple
samples in parallel.
operator can intervene if not all the colored material is captured
in the loading step or does not fully elute from the cartridge in
the expected volume of solvent. For example, if the SPE
cartridge remains colored after the elution step additional
solvent(s) can be added to elute all the color. While fluorous
dyes have been reported previously,6−10 there do not appear to
be any reports of derivatives that also incorporate a reactive
functional group for use as a synthesis support or linker (to use
solid-phase terminology). Although there are many permuta-
tions for a trifunctional molecule comprising a fluorous tag,
chromophore, and linker, it is important to retain the fluorous
character and high solubility in organic solvents that character-
ize conventional tags. Permanently charged or readily ionized
dyes and composite molecules with a large number of hydrogen
bond donors were therefore avoided in the prototype design
illustrated in Figure 1. Thus, the nitrogen atom of aniline 1 is
substituted with a fluorous tag via electronically insulating
methylene groups and with a dialkoxybenzaldehyde linker
analogous to those used in solid-phase chemistry11,12 and
previously incorporated into aldehyde 3,13 and related fluorous
compounds.14 Chromophores can then be appended by
electrophilic substitution in the aniline ring of 1. In this
Note, the synthesis and properties of azo dye derivative 2 are
described as well as applications in two synthetic schemes
facilitated by visual monitoring of the F-SPE process.
Received: December 28, 2011
Revised: January 24, 2012
Published: February 9, 2012
In principle, the partition and subsequent elution of a
fluorous-tagged substrate from an SPE cartridge can be
© 2012 American Chemical Society
150
dx.doi.org/10.1021/co2002153 | ACS Comb. Sci. 2012, 14, 150−154