Switchable Nucleophilic Site Enables Expedient Synthesis of CF3-Containing Thiazoles and Allenes from 1,3-Enynes

Typically, trimethylsilyl isothiocyanate (TMSNCS) is used as a nucleophilic thiocyanate building block (S--C=N) that reacts with various electrophiles. However, it has been less explored as a source of isothiocyanates ((-NCS)-C-=-S-=), which can usually be converted by thermal isomerization of allyl or propargyl thiocyanates. Achieving a method with precise site control is even more challenging. Here, we demonstrate an approach that uses metal catalysts to control switchable nucleophilic sites and provide a strategy to construct CF3-containing thiazoles and allenes via the multicomponent reaction of 1,3-enynes, TMSNCS, and electrophilic trifluoromethyl reagent. In the presence of inexpensive Fe(III) or Cu(II) catalysts, the current reaction is practical and convenient, compatible with various substrates bearing sensitive functional groups that can be readily transferred to more complex scaffolds. The biological evaluation showed that two of the developed CF3-containing thiazoles exhibited dramatic inhibitory activities for three human cancer cell lines beyond those of 5-fluorouracil. Both compounds increased the level of reactive oxygen species in MCF-7 cells, which is believed to be an early step in tumor cell apoptosis.

Automated summary

This study demonstrates a method using metal catalysts to control switchable nucleophilic sites, and provides a strategy to construct CF3-containing thiazoles and allenes via a multicomponent reaction. The reaction is practical and convenient, compatible with various sensitive functional groups and shows high inhibitory activities against human cancer cell lines. The CF3-containing thiazoles increase the level of reactive oxygen species in MCF-7 cells, suggesting a potential mechanism for inducing tumor cell apoptosis.