Novel OSM106-sulfamate analog - progress and challenges #31
Description
I am currently working on a novel OSM-S-106 sulfamate analog based on a previous OSM-S-106 synthetic routes that incorporates an idea from a recent publication from Prof. Tilley's group.
The main step is the synthesis of OSM-S-106 sulfamate analog from our core thienoprimidine (yellow circle in the Box). I have attempted this synthesis but have encountered some problems:
1) Sulfamate decomposition
Miyaura borylation between bromophenyl sulfamate and B2pin2 was carried out in preparation for the subsequent Suzuki reaction (Box, Thread 1). However, the LCMS/NMR analysis of the reaction product indicates the sulfamate has degraded to an alcohol. This paper and this paper also suggests that sulfamates can undergo this kind of transformation under basic conditions. In our hands, varying the temperature (100 °C - 140 °C) under microwave conditions gives the same phenol elimination product. I think the microwave conditions might be too harsh for this reaction so I'm going to try the borylation under normal heating conditions (TLC monitoring). Overall, it will be interesting to see the stability of the sulfamate under the basic conditions (with PdCl2(dppf)) of the borylation.
2) Sulfamate as a leaving group in the Suzuki reaction
This paper showed the sulfamate can act as a pseudohalide and became a good Suzuki substrate with a Ni catalyst at 110 or 130 °C (we used a Pd catalyst under 90 °C for the Suzuki reaction). We were a little concerned that the sulfamate might be able to take part in the Suzuki coupling, generating byproducts. But I couldn't find any reference that used a sulfamate as a substrate of Suzuki reaction with Pd catalyst. Is anyone familiar with the use of sulfamates in Pd-catalysed Suzuki reactions?
In general, I believe it is worthwhile to test the reactivity of the Suzuki substrates (above figure, Thread 2). Will the boronic acid react first with the bromine or with the sulfamate? Will I obtain the same product if I reverse the boronic acid and bromine substrates? Will the sulfamate eliminate to give the alcohol at 90 °C?
Please feel free to make any more suggestions here :)