Variations for Special Circumstances

In a new publication submitted to the Handbook of Fluorous Chemistry, Lindsley and Leister of the Department of Medicinal Chemistry at the Merck Research Laboratories, summarize three variations to the light fluorous scavenging paradigm, based on reaction conditions and the nature of the fluorous scavenger employed (Handbook of Fluorous Chemistry, 2003, submitted.)

Often times, a solution-phase tertiary amine base may be employed in a fluorous scavenging reaction to either deprotonate the scavenger or to sequester acid generated during the reaction.  Since the amine base will co-elute with the desired organic product resulting in contamination, the base must be removed prior to Fluorous Solid Phase Extraction (F-SPE).  The first variation to address this issue required a mildly acidic aqueous workup prior to F-SPE to reprotonate the excess scavenger and remove the solution-phase tertiary amine base (Figure 1).

Then, standard F-SPE of the organic layer provides the desired product in high yield and purity.

A second common variation involves the replacement of the solution-phase tertiary amine base with an excess of a polymer-supported tertiary amine base.  Under this protocol, the aqueous workup can be avoided and the F-SPE step also removes the polymer-supported base, affording similar yield and purity (Figure 2).

The third variation centers on the properties of the fluorous reagent/scavenger.  During the course of a scavenging reaction, the fluorous reagent/scavenger can be converted into a charged species such as salt.  When this occurs, the scavenger may co-elute with the organics during the F-SPE step, as the salt will have reasonable solubility in aqueous methanol, leading to impure products.  Therefore, when employing a polar, basic scavenger and/or a fluorous tertially amine base, a mixed sorbent SPE cartridge (an ion exchange column-SCX or SAX fitted inside a FluoroFlash® SPE cartridge) served to neutralize amine hydrochloride salts and cleanly separate fluorous-tagged from untagged organics.

Under this protocol, the crude reaction could be applied directly to the mixed sorbent SPE cartridge and thereby avoid both an aqueous workup and the diminished kinetics of polymer-supported reagents.