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The OSM team started work on the fourth series of compounds, the triazolopyrazines, in September 2013. The team is focused on the synthesis of compounds featuring ether or amide linkages to the triazolopyrazine core (see below).
The most elegant and efficient way to synthesised the amide compounds would be to use a common intermediate A, required for an established route to ether compounds of type B. Direct carbonylation of A could lead to the synthesis of carboxylic acids/ester intermediates (C) for diversification into different amides. Direct amide formation should also be possible, but for the moment bulk synthesis of useful intermediates would be preferable.
The reaction of aryl-X compounds to form carboxylic derivatives was pioneered by Heck et al. in the 1970s but great progress on metal catalysed carbonylation of aryl-x groups has been made in the last ten years, in particular with respect to Pd-catalysed reactions. (See ACIE review by Anne Brennführer, Helfried Neumann, and Matthias Beller DOI: 10.1002/anie.200900013).
The team received some details of preliminary attempts at carbonylations of compounds of type A by the CRO (see slide below).
The CRO were not successful in their efforts but the OSM team are confident that carbonylation of A could be achieved. For the moment, we don't have enough synthetic resources to explore this reaction and are therefore working on amide synthesis starting from compound 1 (as seen on this slide) as this synthesis will hopefully not require as much optimisation as the carbonylation and can also be performed by undergraduates - the use of expensive transition metal catalysts and CO are not always possible.
Therefore, we are looking for potential collaborators who would like to develop the direct carbonylation of triazalopyrazine chlorides. If you think that you or your lab can help please join the team. Comment below or tweet us at @O_S_M. We prefer to avoid email but if that's easier then drop us a line at firstname.lastname@example.org.
The OSM Team
"Carry your acid as a furan to the end and blast open with permanganate or RuCl3/NaIO4 in the final step. Depending on your Ar group, may trash your compound, but could be quick to try. The heterocycle itself should be stable enough. Would have to start from the following compound: ClC1=NC(C2=CC=CO2)=CN=C1. Should be an easy Suzuki to make it from the 2,6-dichloro.
If you want to stick with the carbonylation route, I’d recommend reading: JOC, 2008, 7096. You probably need to use an alkyl substituted bis-phosphine ligand as described in this paper for this coupling. The phenoxide product is also probably even more useful to you than the acid you’re trying to make, because it can obviously get you to your amides directly."
Also posted this here.