The unusual impact of benzopinacolone on 4-phenylthiosemicarbazide, a nucleophile with alpha-effect

• Steeve A. Adjibode

  English

  Author

• Oscar Jacques H. Poupaert

  English

  Author

We are interested in developing new chemical entities with a thiohydrazide (C=S) NHNH or thiosemicarbazide NH(C=S) NHNH central template
flanked on both sides by lipophilic aryl moieties. This is part of a medicinal chemistry-driven drug discovery program that aims to synthesize new
topically-acting trypanocidal chemotherapeutic agents to treat African trypanosomiasis. Within this framework, benzopinacolone was discovered to
function as an unusual acylating agent through an addition/elimination mechanism. This involved adding a thiosemicarbazide derivative as the
nucleophile, forming a tetrahedral adduct, and then removing a trityl anion group as the leaving group. This process was likely aided by an
anchimeric effect involving intramolecular hydrogen bond formation involving the thioureido side-chain. Here, the current serendipitous finding
should be viewed as the initial spark, and research is currently focused on unraveling the intricate workings of this remarkable chemical pathway; in
this reaction, the rate-determining step involves the unusual breaking of a carbon-carbon bond (with carbon acid as the leaving group), and the
decomposition of the intermediate tetrahedral adduct is what ultimately leads to the unexpected N-thiobenzoyl-thiosemicarbazide.

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