<i>Ipso</i>-Chlorosulfonylation of Calixarenes:  A Powerful Tool for the Selective Functionalization of the Large Rim

In our quest for the elaboration of supramolecular models of metallo-enzyme active sites, we became interested in developing new methodologies for the selective functionalization of the large rim of calix[6]arenes. Here, we describe a novel reaction, i.e. the <i>ipso</i>-chlorosulfonylation of calixarene derivatives. The process has been found to be highly efficient, selective and versatile. The regioselectivity is controlled by the nature of the <i>O</i>-substituents at the small rim. Indeed, when <i>O</i>-alkylated by a protonable imidazole group, the aromatic rings are deactivated toward an electrophilic attack and the anisol units can be selectively <i>ipso</i>-chlorosulfonylated under mild conditions (rt). Performing the reaction at a higher temperature allowed the <i>per</i>-chlorosulfonylation to take place. Hence, the synthesis of various sulfonate and sulfonamide derivatives is reported. Finally, a combination of <i>ipso</i>-nitration and chlorosulfonylation allows the <i>per</i>-functionalization of the aromatic units at the large rim in selective alternate positions. Overall, this novel methodology opens new routes to a variety of calixarenes, allowing the tuning of their physical properties without drastically altering their hydrophobic conic cavities.