Late stage fluorination

Due to its unique properties, fluorine is becoming more popular in drug discovery. However direct fluorination of substrate remains challenging. The main strategy to synthesize fluorinated analogues of a lead compound still relies primarily on using fluorinated building blocks in the known lead synthesis. This strategy is limited by the availability of the fluorinated building block and the complexity of the synthesis.

In this context, late stage fluorination can be a powerful tool to access fluorinated analogues of lead compound that won’t be readily accessible otherwise. When standard fluorination chemistry uses pre-activated position with for example a hydroxyl or tin derivatives, late stage fluorination requires the ability to substitute a poorly reactive hydrogen with a fluorine.

In the past 10 years numerous researchers developed methods to allow C-H bond activation and hydrogen substitution with primarily hydroxyl to mimics phase 1 metabolism but also with acetoxy, methoxy, alkyl groups and finally fluorine.

The C-H activation chemistry is divided in 2 main categories: directed chemistry and radical chemistry. Recently C-H fluorination has been described using both type of chemistry.

Ligand directed mechanism


Radical fluorination


When directed fluorination is primarily based on palladium catalytic systems, radical C-H fluorination is described with iron, manganese or tungsten catalysts. Note that iron and manganese catalysts are activated by an oxidant and tungsten is activated by light.


Examples of C-H fluorination
Manganese catalyzed fluorination


Groves,  Science, 2012, (337) 1322.

Iron catalyzed fluorination


Lectka,  Org. Let., 2013, (15) 1722.

Tungsten catalyzed fluorination


Britton, Angewante 2014.

Palladium catalyzed fluorination


Sanford, et. al., Organic Letters, 2012, 4094.


Which fluorination chemistry should I select for my compound?

It is very difficult to predict at which position a C-H fluorination will be done. In a standard drug compound there are often more than 10 carbons that bear one or several hydrogens. The C-H bond can be activated by a nearby chemical group such as an amine, a ketone or an amide it can also be part of an aromatic systems such as a pyridine.

The range of C-H bond reactivity affects the fluorine distribution on the compound structures. Also the type chemistry has different affinities to each type of C-H bond. For example directed fluorination chemistry and radical C-H abstraction usually don’t produce the same analogues.



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