Copper-Mediated Cyclization of Propargyl Thioimidates to Functionalizable Dihydrothiazoles

Heterocyclic structures are a major component of many organic molecules of interest, of which 5-membered nitrogenic rings (such as pyrrole, oxazole, thiazole, and imidazole) are a significant portion. Presented here is a novel method for the synthesis of functionalized thiazole rings from propargyl thioimidates mediated by catalytic copper (I) iodide, building on prior work with oxazole formation. Potential routes to pyrrole and imidazole cyclizations are also briefly investigated and discussed. A synthetic route for the propargyl thioimidate substrates has been developed using the nucleophilic attack of a thioimidate sulfur on propargyl bromide, in contrast to utilizing propargyl alcohol to attack a nitrile to form the analogous propargyl imidate. Initial attempts at cyclizing propargyl thioimidate substrates with copper (I) iodide catalyst were promising, with yields ranging from 50-95% on a 0.35 mmol scale, with the caveat that the nonaromatic products are rapidly tautomerized to their aromatic forms in the presence of acid or base. Further published optimizations of this reaction scheme have increased yields to above 90% for most substrates. Diversification to pyrrole and imidazole cyclizations has proven ineffective at this time, both in preparation of the initial substrates and the cyclization reactions themselves. Computational studies of several of the substrates in question indicate that the oxazole rings have a lower Gibbs free energy than their pyrrole analogues, explaining their relative ease of formation from a thermodynamic perspective. Orbital visualizations suggest favorable conformational differences in the oxazoles as a possible cause, where (nO ? ?*C-N) and (nO ? ?*C-N) electronic donation in the imidate moiety stabilizes the propargyl group during cyclization.