Ishikawa’s Reagent

Mechanism + Description

The reagent works by activating the alcohol followed by displacement of the amide-forming leaving group by HF.

General comments

Ishikawa’s reagent (N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine) is available commercially or often made in situ by condensing perfluoropropene in to a vessel with 1 eq of Et₂NH or a higher mol wt secondary amine like piperidine or morpholine. The reagent is used to convert alcohols to fluorides under mild conditions, and often goes with good inversion with chiral alcohols. The reagent is selective for alcohols and does not react with ketones or aldehydes. TFEMDA and Yarovenko’s reagent are related fluorinating agents. Allyl and propagyl alcohols may give rearrangement products.

Key references

Akio, T.; Hiroshi, I.; Nobuo, I. F-Propene-Dialkylamine Reaction Products as Fluorinating Agents. Bull. Chem. Soc. Jpn. 1979, 52, 3377-3380.  

Petrov, V. A. α, α- Fluoroalkyl(Alkenyl) Amino Reagents (FAR) – Recent Development. In Advances in Organic Synthesis; Atta-ur-Rahman, Laali, K. K., Eds.; Advances in Organic Synthesis Volume 2; Bentham E Books: 2007; pp 269-290.

Kubota, T. Fluorine Chemistry from Professor Nobuo Ishikawa Group. J. Fluorine Chem. 2000, 105, 193-196.

Watanabe, S.; Fujita, T.; Sakamoto, M.; Endo, H.; Kitazume, T. Fluorination of aromatic α-hydroxy esters with N, N-diethyl-1,1,2,3,3,3-hexafluoropropanamine. J. Fluorine Chem. 1990, 47, 187-192.

Relevant scale up example

None found.