Design and Synthesis of Azacyclophanes

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Azacyclophanes are host compounds suitable for complexation of guest in aqueous solution. Various type of azacyclophanes were investigated, however, 5-azacyclobenzylene derivatives have not been synthesized. We have already prepared 5-silacyclobenzylene compounds, which have a unique C_2 symmetrical structure. Therefore, a quatemary ammmonium salt (N,N-dialkyl-5-azacyclobenzylene) is promissing to be used as a chiral phase transfer catalyst. On the other hands, studies on biological activities of azacyclophanes have not been reported so far. We tried to construct the 5-azacyclobenzylene skeleton by two pathways. At first bis(6-bromoveratryl)veratrole, a useful synthestic block, was apllied to react with benzyl amine in the presence of palladium catalyst to construct the target skeleton, however, it failed to obtain 5-azacyclobenzylene derivatives. Second tactics involved employment bis(2-hydroxy-methylphenyl)amine as a starting material. 4-Chlro-2-(2-hydroxymethylphenyl)aminobenzyl alcohol, readily prepared from Lobenzarid【○!R】, was treated with veratrole under acidic conditions to give successfully 5-azacyclobenzylene derivative (1). The reaction with excess veratrole afforded an acyclic bis(veratrylphenyl)amine, cyclization of which into cyclotetrabenzylene with formalin under acidic conditions was tried to form bicyclic cyclophane unexpectedly. The structure of the product was not disclosed yet. The bis(veratryl-phenyl)amine was methylated with formalin and NaBH_4 to give the corresponding N-methyl derivative, cyclization of which is now in progress. No antifungal activity of azacyclophane (1) to five types of funngi was observed by the disc method. Behaviors were investigated according to Irwin's method in ddY strain 5 week mice. As a result, writhing was observed during by the injection with the cyclic amine (1).