Date of Award
Doctor of Philosophy
J. H. Wood
H. Johnson, William T. Smith, George P. Mueller, H. K. Garber
Introduction: The isolation of epinephrine from the medulla of the suprarenal gland and the discovery of its amazing therapeutic effects have stimulated intensive research on the synthesis of compounds possessing the basic skeleton of 2-aminoethyl-benzene. The investigation in the past forty years have culminated in the preparation of a large number of this type of amine which are pharmacologically classified as "sympatho-mimetic" or "pressor" agents because they generally act on the sympathetic nervous system and cause in increase of blood pressure. However, the 2-aminoethylbenzene derivatives most thoroughly studied have been those whose molecules possessed only one aminoethyl side chain per benzene nucleus.
It was von Braun who first reported the synthesis of 1,2-bis(2-aminoethyl)-benzene in 1916 and further noted that this substance did not show the usual sympathominetic activity of 2-aminoethylbenzenes. No other investigation on the derivatives of bis-aminoethylbenzenes has been reported until quite recently when Wood and Gibson prepared a series of p-(2-aminoethyl)-hydroquinones. Pharmacologic assay by the Lilly Research Laboratories of Eli Lilly and Company showed that these compounds possessed little activity. Since the compounds in this series were symmetrically constituted, it seemed desirable to prepare several bis-(2-aminoethyl)-benzenes in which the two 2-aminoethyl groups were unsymmetrically placed with respect to each other and with respect to other substituents of the molecule. Accordingly, M. A. Perry instituted a program in this laboratory that covered the synthesis of o- and m-bis-(2-aminoethyl)-benzenes. At approximately the same time, this investigation was started with the purpose of developing procedures that would lead to o-, m- and p-bis-(2-aminoethyl)-benzenes whose molecules possessed substituents, preferably the hydroxy or methyl or both, on the 1- and 2-carbons of the ethylamino side chain. In addition to this objective, this investigation was started with the purpose of developing suitable methods for obtaining the intermediates which were necessary in the synthesis of bis-(2-aminoethyl)-benzenes. From this point of view, chloro-methylation reactions and the Sommelet reaction were to be studied. Finally, the new amines which resulted from these investigations were to be prepared in quantity for submission to the Lilly Research Laboratories for pharmacologic testing.
Tung, Ching Chen, "The Synthesis and Pharmacologic Activity of Some Bis-(2-aminoethyl)-benzenes. " PhD diss., University of Tennessee, 1951.