Tetramisole-derived molecules constitute an important class of organocatalysts for the kinetic resolution of a variety of oxygen and nitrogen nucleophiles. Generally, these serve as chiral nucleophilic acyl transfer agents. The most popular variants thereof include benzotetramisole (BTM), homobenzotetramisole (HBTM), HBTM-2, and HBTM-2.1. These catalysts are available in high enantiomeric purity because the synthesis precursors are derived from amino acids or products of a proline-catalyzed enantioselective Mannich reaction. A crucial step in the reported procedures for the synthesis of catalyst products requires addition of an amino alcohol to 2-chlorobenzothiazole to give a 2-aminobenzothiazole. This addition reaction requires prolonged heating with a tertiary amine solvent, and the reported reaction times vary substantially, ranging from 24–70 hours. We have optimized an alternative procedure for preparing this important class of molecules that i) can be accomplished from the same amino alcohol precursors in six hours for all catalysts, ii) is highly efficient (i.e., yields up to 95%), and iii) is amenable to new analogues. Additionally, the entire procedure is completed in one-pot and uses standard reagents. A key feature of the protocol includes sequential halogen mediated ring formations. Specifically, an initial bromide-mediated benzothiazole formation is followed by an iodine-mediated cyclization to form the imidazoline. In this presentation we will discuss our efforts related to i) reaction condition optimization, ii) the preparation of new HBTM analogues, and iii) application of these new analogues to reportedly difficult kinetic resolutions.

One-pot synthesis of tetramisole-derived organocatalysts from amino alcohols

253rd National Meeting (2017)

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