Cone p-aminocalix[4]arenes enriched with 'clickable' alkyne or azide functionalities

Efficient approaches have been developed for the synthesis of heteromultifunctional cone calix[4]arenes containing four amino groups at the wide rim and one, two or four propargyl or 2-azidoethyl groups at the narrow rim of the macrocycle, which can be used for expanding functionalization of the calixarene core in the well-known amine acylation (or similar reactions) and CuAAC 'click' reactions. Two different strategies were implemented to obtain propargylated and 2-azidoethylated p-aminocalixarenes. In the case of propargylated calixarenes, sterically crowding silyl protection was introduced into the alkyne groups of p-tert-butylcalix[4]arene (multiple) propargyl ethers, and the resulting compounds were ipso-nitrated followed by reduction of the nitro groups. To prepare 2-azidoethylated macrocycles, the ipso-nitration/reduction sequence was applied to p-tert-butylcalix[4]arenes containing 2-tosyloxyethyl groups at the narrow rims followed by replacement of the tosyloxy groups with azide ones. In all cases, p-aminocalix[4]arenes were obtained as the readily cleavable tert-butoxycarbonyl (Boc) derivatives, which was crucial for certain transformation and purification steps. To confirm the functionalization capabilities of the five obtained multifunctional calixarenes, they were reacted with excess benzyl azide or phenylacetylene, taken as representatives, under copper(I) catalysis, resulting in the narrow-rim triazolated macrocycles. By removing the Boc protecting groups and involving the free amino groups in reactions with p-tolyl isocyanate, a series of narrow-rim triazolated tetraureacalix[4]arenes was obtained. Examination of the ¹H NMR spectra of the tetraureas in CDCl₃ showed that in most cases triazole heterocycles do not intervene the formation of homo- and heterodimeric capsules by these compounds. Thus, considering the synthetic value of CuAAC and amine transformations, p-aminocalix[4]arenes enriched with alkyne or azide functionalities can be readily used as multifunctional platforms to obtain even higher functionalized macrocycles. As an example, they can be used for the preparation of sophisticated supramolecular assemblies with homo- or heterodimeric calixarene cores and virtually any functional units attached to them via triazole groups.