ChemFiles Volume 4 Article 9

In a typical Mitsunobu reaction between an acidic pronucleophile and an alcohol promoted by diisopropylazodicarboxylate (DIAD) and triphenylphosphine, the desired product is contaminated by reagent derived by-products, phosphine oxide, and hydrazide. F-triphenylphosphine (# 07026 ) and F-DIAD (# 68333 ) can be used in traditional solution-phase Mitsunobu chemistry.[1] The by-products of the reaction are easily separated from the desired product by performing a quick fluorous solid-phase extraction over FluoroFlash® silica gel.[2] The original fluorous azodicarboxylate, F-DEAD, worked well for carboxylic acid and phthalimide pronucleophiles, but generally less well for phenols and other higher pKa acids. By employing F-DIAD reagent, it is now possible to conduct fluorous Mitsunobu reactions with almost all classes of pronucleopohiles including phenols.

Other fluorous phosphine analogs with increased number of fluorine atoms may be used. Those with the highest fluorine content are suitable for reactions and separations under biphasic conditions. The phosphine oxide residue may be removed by liquid-liquid extraction as an alternative to SPE.

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  1. Dandapani, S.; Curran, D. P. Tetrahedron 2002, 3855–3864;
  2. Curran, D. P. Synlett 2001, 1488.

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