Proximal regioselectivity of the O,O′-dialkylation of tetrahydroxyketocalix[4]arene

The only dialkylated products obtained in the reaction of tetrahydroxyketocalixarene 2a with MeI/ K₂CO₃ or PhCH ₂Br/K₂CO₃ are the corresponding proximal (i.e., 1,2) O,O′-dialkyl ethers, in contrast to the parent tetrahydroxycalix[4] arene 1a which affords the distal (1,3) dialkyl ether derivatives. Pairs of geminally alkylated phenoxy groups in the conformationally rigid dibenzylated and tetrabenzylated derivatives are oriented in an anti fashion. These results can be rationalized assuming that the 1,3-alternate arrangement of the rings preferred by 2a is adopted during all the intermediate stages of the alkylation. The NMR spectra (in CDCl₃) of the monomethyl, dimethyl, trimethyl, and tetramethyl ether derivatives of 2a are in agreement with a 1,3-alternate conformation.