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Microwave Fluorous Chemistry: Faster Synthesis + Faster Separation

Fluorous synthesis under microwaves can create many new opportunities for synthetic chemists. Benefits include:

  • Fast synthesis by coupling microwave reaction with fluorous separation
  • No swelling or thermostability issues compared to solid-phase microwave reactions
  • Possibility of solvent-free reactions
  • Applicability to all fluorous techniques including use of fluorous reagents, catalysts, scavengers, tags, and protecting groups
  • High-throughput synthesis possible by parallel or automated sequential microwave reactions combined with F-SPE in a plate format

 

How Does Microwave-Assisted Fluorous Synthesis Work?

Fluorous Microwave Rxns Explained.

Microwave irradiation is a new method of energy transfer.[1] Compared to traditional oil bath heating, microwave irradiation can significantly reduce reaction times and improve yields. A typical microwave reaction requires less than 10 min for completion. However, microwave technology does not directly address the separation issue, which is typically the bottle-neck of high-throughput synthesis. Fluorous techniques allow the chemist to overcome this bottle-neck by enabling quick purifications. In this case, fluorous solid-phase extraction quickly separates the reaction mixture into fluorous and non-fluorous fractions. The desired fraction is concentrated and then the product is characterized. The whole synthesis process can be finished in less than one hour, which gives fast turn around for compound production or reaction optimization (Fig.1).

Basic Techniques

Monomode Microwave Cavity and Fluorous Solid-Phase Extraction

Fluorous Microwave Rxns Explained.

Microwave-assisted fluorous synthesis requires a monomode (focused) microwave reactor for reaction and a solid-phase extraction manifold with FluoroFlash® cartridges for separation (Fig. 2). If the reaction is conducted in small amount of solvent or under solvent free conditions, the reaction mixture can be directly loaded onto the cartridge. Elution with a fluorophobic solvent such as 80/20 MeOH/water for the non-fluorous fraction followed by a fluorophilic solvent such as MeOH, MeCN, or THF for the fluorous fraction provides materials of purity >90%.


Basic Applications

Fluorous Suzuki Coupling

Fluorous Suzuki Coupling. The microwave-assisted fluorous Suzuki reaction couples a fluorous sulfonate with a boronic acid (Fig. 3).[2] In this example, a commercially available phenol is converted to a sulfonate by reacting with C8F17 perfluorosulfonyl fluoride. Similar conditions as in traditional thermal Suzuki couplings are applied to the microwave reaction except the reaction temperature is higher (100ºC) and the reaction time is much shorter (10 min). Fluorous solid-phase extraction is employed to separate the coupling product from the cleaved fluorous tag. The biaryl product is collected from the MeOH/water fraction.






Advanced Applications

Multi-Step Reactions

Multi-Step Reactions. The benefit of the fluorous solid-phase extraction can be maximized by designing a multi-step synthesis. The tagged substrate can carried through additional transformations before reacting with boronic acids to generate the biaryl C-C bond or reacting with formic acid to give a traceless product (Figure 4).[2] At the step of condensation, cycloaddition, and Suzuki coupling, new diversity points can be introduced by running parallel reactions.










Selected References

  1. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225. [Back to Text]
  2. Zhang, W.; Chen, C. H.-T., unpublished results. [Back to Text]
  3. Run under license to US patent 6,136,157 and European patent No. 0901 453 held by Personal Chemistry