Frequent readers know I have voiced my concern about fluorinated organic compounds, especially those containing aliphatic fluorides, from time to time. New fluorination recipes pop up all of the time, and more and more pharmaceuticals contain one or several very stable C-F bonds, which may or may not spell trouble for future generations. In the light of this, it is encouraging to see that people are indeed making progress in tearing C-F bonds apart too.

Graphical abstract

I very much enjoyed reading this recent article, Org. Lett. 2012, ASAP (DOI: 10.1021/ol300977f), in which the authors demonstrate several different ways of turning aliphatic fluorides into leaving groups; in this case benzylic ones.

Under palladium catalysis, it was possible to knock out benzylic fluorides with carbon, nitrogen, oxygen and sulfur nucleophiles, in good to excellent isolated yields. That is pretty impressive. The substitution seems to proceed by retention of configuration, which may shed some light on a plausible mechanism, as when a chiral benzylic fluoride upon treatment with morpholine as a nitrogen nucleophile produced an enantio-enriched product.

Moreover, the authors show that benzylic fluorides can effectively be used as coupling partners in Suzuki type reactions, which further broadens the usefulness of the compound class.

A totally awesome example of site selectivity is demonstrated in Scheme 2 (middle versus bottom rows).

Site selectivity

I can really recommend reading this paper. It is great.

 

7 Responses to C-F bond breakage

  1. See Arr Oh says:

    I am forever amazed when chemists develop practical bond-breaking reactions. Nature does this all the time, but we’re still learning how to do it in a controlled fashion.

  2. milkshake says:

    if you are doing medicinal chemistry (I suppose you do) please keep in mind that benzylic fluorides are not quite innocuous, they can be fairly electrophilic. I have seen facile elimination of F(-) from difluoromethyl and trifluoromethyl- substituted anilines having the CHF2 (or CF3) in ortho-position to aniline. This produces quinomethide-imine species that are very reactive (similar to PMB cation) and provide either reaction products of F displacement or hetero-Diels Alder produce depending on the reaction partner. With very acidic anilines like 5-CHF2 or CF3 substituted 4-aminopyridine this elimination happens readily even with a mild base such as K2CO3

    • drfreddy says:

      As tainted medicinal chemists know, the chemical fate of an API in vivo is always a billion dollar lottery.

      How many times have not a rat pissed out a metabolite 20 mins after administration, which then takes a team of scientist half a year to isolate, characterize and synthesize.

      I am well aware that benzylic fluorides can be labile in vivo. However, they are usually frickin rigid inside a roundbottom flask.

  3. CatalysisAlex says:

    As fascinating as this is, it is still kind of ironic, considering how much effort is put in, especially by medicinal chemists, to make the C-F bond….

  4. […] which is not very common, although benzylic fluorides are somewhat reactive). This article was also featured on Synthetic […]

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