C-H activation showcase

C-H activation has been a hot subject for the last few years with many groups investing much effort in removing the need for organo-metallic derivatives that can prove a challenge of their own to generate. Despite many efforts in what sometimes looks more like ‘black art’ than planned selectivity, the direct arylation of pyrazoles has been one of the toughest challenges of the past 10 years. The likes of Daugulis and Sames have established methodologies involving Cu catalysis and SEM directing groups to enable the direct arylation onto pyrazoles.

 A recent publication from Doucet’s group at the Université de Rennes showcases the introduction of a sacrificial heteroatom to address the selectivity of aryl moieties onto pyrazoles by direct arylation.


The initial C-H activation is worth a few words here as the reaction is catalysed by a phosphine free palladium used in very low loading (0.1%). A considerable advantage over the typical conditions, especially as such processes find their way into pilot plants and commercial routes. No mention however as to why the reaction undergoes C-H activation with such a system. Also of interest, the authors claims the arylation proceeds via a Concerted Metalation Deprotonation (CMD) mechanism. Although there are no explanations, it is interesting to note that in this case pivalic acid, normally added to lower the energy of the C-H bond cleavage, is not used in this CMD reaction.

The reaction prefers para- and meta- electron withdrawing aryl bromide substituents with yields mostly ranging in the 70 to 80%.


Of most interest is the direct arylation of pyridyls, quinolones and isoquinolines, all obtained in high yield. A real ‘tour de force’ if you have ever tried to introduce a boron to either a pyridyl or a pyrazole without suffering subsequent protodeborylation during the cross coupling.

Dehalogenation in the presence of 5% Pd/C enables the further direct arylation at the C-5 position, this time using a palladium with a phosphine ligand.


Overall, a good example of how powerful the C-H activation methodology can be in coupling hetero aromatics moieties together

This article can only lead to a comparison to the excellent Sames’ article published in JACS (previously mentioned in my introduction and to which the author also refers to) a few years ago. Sames used nitrogen protected SEM group to direct the selectivity to the adjacent carbon.




7 thoughts on “C-H activation showcase

  1. This chemistry was used for the direct arylation of SEM-protected-3,4-disubstituted pyrroles at Novartis. Interestingly, we obtained C2-selectivity with C-H activation and C5 selectivity with a lithiation-borylation-Suzuki approach.

  2. “A real ‘tour de force’ if you have ever tried to introduce a boron to either a pyridyl or a pyrazole without suffering subsequent protodeborylation during the cross coupling.”

    A good screen of buchwald ligands, solvents and bases should fix that

  3. The point I was trying to get across is that if you need to go through the suzuki pathway (and many chemists do as C-H activation is still in its relative infancy) then protodeborylation is not so much as an issue as it used to be in the past.

    • Point taken. From previous experience, Suzuki cross couplings with pyrazoles and imidazoles (where the boron is attached to the 5-membered het) can be very costly despite extensive condition screening (Kg-lab) and C-H arylation has now become a viable route in such cases (again in Kg-lab). The publication from Doucet seems to demonstrate a nice example there where the methodology can be applied.

  4. Indeed it does, guess I should have praised the work first and then made my comment. I find this particular type of C-H activation most interesting because it does not require any oxidant (O2, Cu(OAc)2, diacetoxyiodobenzene, etc). Even more interesting is that it does not require the presence of an acid as in Sames work. Guess the acetates on the palladium can do the same job. Great article, thanks for sharing

  5. Pingback: Blog Plug: Sussex Drug Discovery « Chemtips

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