Rational synthesis for all All-homocalixarenes

Calixarenes and related compounds are established scaffolds useful as ligands and very popular as building blocks for molecular design. At the same time, the use of these compounds is virtually always defined by the ability of researchers to prepare them efficiently in useful quantities, and in a controlled fashion. As an example, calix[4]arenes, calix[6]arenes, and calix[8]arenes gained popularity very quickly after Gutsche et al. developed and perfected onestep methods for their preparation. Fitting geometry, namely appropriate ring size and dominant conformation, are of paramount importance in most macrocycle applications, yet the overwhelming majority of publications still only report modifications of the three above-mentioned easily prepared calixarene cores. Homocalixarenes have been a subject of scientific interest for a couple of decades. Whereas calixarenes have only one carbon atom between the aromatic rings, the presence of extra linkers between the aromatic rings allows the tuning of the desired cavity size, symmetry, and conformational mobility of the molecule. All-homocalixarenes have been defined by Vcgtle and co-workers as those in which all aromatic rings are separated by two carbon atoms. All-bis(homocalixarene)s are those separated by three carbon atoms, All-tris(homocalixarene)s separated by four carbon atoms, etc. We use the term homocalixarenes to refer to all calixarenes which have tether lengths greater than one carbon atom for at least one of the tethers and all-homocalixarenes for all calixarenes in which each of the tethers is greater than one carbon atom. The most direct method for the synthesis of all-homocalixarenes is the M ller–Rcscheisen cyclization which gives mixtures of calixarenes in low yields. All-homocalixarenes have also been made in a multistep synthesis by sulfur extrusion upon thermolysis of the corresponding sulfone. Several methods have been used in the synthesis of all-bis(homocalixarene)s, including alkylation of bis(bromomethyl) benzenes with tosylmethyl isocyanide and diethyl malonate, a Claisen rearrangement, and aryllithium/alkyl halide coupling. Larger all-homocalixarenes (n 4) have been made by the reaction of a bis(benzyllithium) with a,w-dihalides, and by the trimerization of a Fischer carbene complex. Homocalixarenes with heteroatoms in the linkers are much more widely studied compared to those with all-carbon linkers. The most popular of these are the bis(homooxacalix[3]arene)s which have enjoyed significant attention from researchers only after the discovery of a direct method for their preparation. Earlier reports from our laboratory have shown that the benzannulation reaction of Fischer carbene complexes can be used to synthesize paracyclophanes with various tether lengths. This chemistry was extended to the synthesis of calix[4]arenes, having various substituents, in a highly regiocontrolled triple annulation, and later extended to chiral calix[4]arenes. The purpose of the present work is to test the viability of this method to serve as a very general approach to all-homocalixarenes, having tethers with any number of desired carbon atoms, on a gram scale. One can envisage that both the homocalix[4]arenes 3 and homocalix[3]arenes 5 can be prepared by the triple annulation method (Scheme 1) involving the formation of two