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7th January 2014 @ 08:18

The OSM team are currently trying to synthesise some triazalopyrazines (series 4) that were found to be promising antimalarial starting points by big pharma.

I (Alice in Mat Todd's group at the University of Sydney) am currently attempting to resynthesise MMV670652 in order to confirm the activity of the racemate and subsequently determine the activity of each enantiomer following resolution.

I have been following a procedure provided by the CRO who had worked on these compounds. (The synthetic route and target are described in more detail here and preparative data found within:


The CRO used Freon gas to difluoromethylate AEW 103 (alcohol SM shown below) but unfortunately, due to limitations on the availability of Freon-22 in Australia, the team need to find an alternative method for this transformation:


A review by Jinbo Hu, Wei Zhang and Fei Wang (DOI: 10.1039/b916463d) revealed a variety of methods for selective difluoromethylation and included a chapter on electrophilic difluoromethylation. 

'The most widely used method for the incorporation of a CF2H group into nucleophiles (such as oxygen-, nitrogen-, sulfur-, phosphorus-, and carbon-nucleophiles) is the reaction of the corresponding nucleophile with a proper difluorocarbene reagent.'

One paper referenced (DOI 10.1021/jm900716v) used trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate or 2,2-difluoro-2-(fluorosulfonyl)acetic acid (shown above) to enable difluoromethylation of 3,6-dimethyl-5-nitropyridin-2-ol (shown below):

The review focused on methods for phenolic difluoromethylation and when surveying the literature, examples of difluoromethylation of aliphatic alcohols were found to be scarce and use free radical methods for the introduction of the group. In September's online meeting, Joie Garfunkel (MMV) suggested the use of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate in combination with a copper catalyst in MeCN at elevated temperatures and pressures (Joie's colleagues had used this method at Merck).

The methods I have attempted so far involved the use of the diflurocarbene generating reagent trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate. I followed the prep. outlined in the paper and began to explore the reaction with copper at room temperature and then in a sealed tube. So far, I haven't had great success with this reaction.

I'm going to try some more conditions and also the use of the more toxic 2,2-difluoro-2-(fluorosulfonyl)acetic acid but would be most grateful for any ideas or assistance in how to get this reaction to work.

Additionally, prefered methods for the trifluoromethylation of the same substrate would be greatly appreciated.

Please post below or tweet me @all_isee and watch this space!



Attached Files
OSM BLOG_difluoromethylation.png
OSM blog dif.png
OSM blog dif2.png
Paper difluoromethylation.png