Synthesis of the Ether Linked Series
The synthesis of members of the ether series has been largely solved by Jo Ubels, as shown below.
The cyclisation was achieved, initially not in the ca. 50% yields reported by the original CRO. Jo Ubels has solved this, with input from others such as a student working with Patrick Thomson, Devon Scott. The boys at Sydney Grammar School have also studied the early stages of the synthesis.
The union of the alcohol fragment with the chloro-intermediate was for a long time not proceeding cleanly, and this was also found by the CRO that first reported this route. Jo Ubels' lit survey found conditions involving a crown ether that has worked reliably. There have been periodic discussions about which alcohols to employ in the resulting synthetic scheme (post from April 2014, GHI174).
A synthetic challenge was the efficiency of the oxidative cyclization to form the triazolopyrazine. There was much discussion of the use of oxidants such as PIDA and chloramine T (Overview GHI 206) as well as the possibility that hydrazone isomers were cyclising at different rates (both Github Issue 97).
Some of the ether compounds contain a stereogenic centre in the benzylic position - structures are in the SAR section above, and the syntheses of these are dealt with in the stereochemistry page of this wiki.
Generally, we have used one of the following three methods for the SnAr attachment of the alcohol fragment to the monochlorotriazolopyrazine core.
