The synthetic challenge of thioglycolurils

The very high stability of cucurbiturils under harsh acidic conditions and their reported prolific chemistry over more than three decades pose a question: why has no thiocucurbituril been reported to date? Furthermore, although glycoluril is a highly stable, easily accessible precursor of all cucurbiturils, its sulfur analog represents a yet unmet synthetic challenge. The reaction between glyoxal and thiourea was found to stop at the level of dihydroxyimidazolidine-2-thione, which is quite unstable under various acidic conditions. In an attempt to answer these questions, several stable analogs of thioglycoluril, that is, monothioglycoluril, ditolylthioglycoluril, and its diether derivative were prepared and characterized in the hope that they could be employed as building blocks for the synthesis of thiocucurbiturils. Several side products were also obtained that highlight the complex reactivity of thiourea in these reactions. The crystal structures of the above-mentioned thioglycolurils are dominated by networks of hydrogen-bonding interactions. Attempts to co-oligomerize these compounds with formaldehyde clearly suggest that it is impossible to synthesize thiocucurbiturils by the methods commonly used for the preparation of cucurbiturils. Given that thiocucurbiturils are expected to be stable molecules, alternative synthetic strategies that are different from the thermodynamically controlled approaches must be designed. Although glycoluril is a highly stable, easily accessible precursor of all cucurbiturils, dithioglycoluril is still unknown. To answer the question why thiocucurbituril has never been made, we prepared several thioglycoluril derivatives and found that they do not survive the acidic conditions usually needed for the co-oligomerization reaction with paraformaldehyde.