Sulfur Extrusion: Eschenmoser Continuous Flow Style

Ah, back to my old thiolactam days, when I would utilize and Rapaport protocol to extend a pyrrolidine or piperidine out. So I thought this has to be a reaction that has been reduced in a continuous flow manner — low and behold, someone has used this sequence in functionalizing pyrimidines (Beilstein JOC 2011)……..are my med chem colleagues in the house?

As a starting point if you haven’t ever performed these reactions, a scheme for the secondary lactam transformation is shown below and the subst version just below that.

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Using this concept, the transformation was applied to some substituted sulfur-pyrimidines.

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As part of the reaction intensification process, this group found the kinetic profile quickly to go along with the concentration for the residence time and made a small library of compounds (see paper for how the kinetic studies were performed). The tables below indicate the materials to start and corresponding final compounds and their yields.

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The coiled capillary reactor design is shown for the control of temperature and flow. Happy Reading!

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