Mechanism of Autoxidation of 5, 7-Dihydroxytryptamine : Effect of Fluorine Substitution at Positions 4 and /or 6

Abstract

Analogs of 5, 7-dihydroxytryptamine (5, 7-DHT), namely, 4-fluoro-, 6-fluoro-, and 4, 6-difluoro-5, 7-DHT's (30a-c) were synthesized starting from 4-fluorophenol (7a), 4-fluorobenzyl alcohol (12) and 2, 4-difluorophenol (7b), erspectively.Regiospecific hydroxylation and formylation ortho to fluoro groups, both via aryllithium intermediates, were made possible by the blocking effect of tert-butyldimethylsilyloxy functions and allowed the conversion of the starting materials to the key intermediates, namely, 3, 5-bis(tert-butyldimethylsilyloxy)-2-fluoro-, 4-fluoro- and 2, 4-difluorobenzaldehydes (11a, b and 19, respectively). The latter were converted in one step to the corresponding benzyloxybenzaldehydes, from which indole-2-carboxylates 22a-c were synthesized via azidostyrenes 21a-c, respectively. Decarbonylation of the indole-2-carboxaldehydes(24a-c) produced from 22a-c in two steps gave 2, 3-unsubstituted indoles 25a-c, respectively.Introduction of the aminoethyl side chains on C-3 of 25a-c via the corresponding indole-3-acetonitriles, and subsequent debenzylation generated the hydroxytryptamines, which were isolated as their creatinine sulfate salts 30a-c, respectively.Cyclic voltammetric studies indicated that like 5, 7-DHT, 30a-c undergo electrochemical oxidation in 1M H2SO4 via the corresponding P-quinoneimine derivatives 31a-c by an electrochemical-chemical-electrochemical (ECE) process. The voltammetrically detectable products of the ECE process appear to be the corresponding 5-hydroxytryptamine-4, 7-dione (6) derivatives 33a-c. The nature of the interaction of dissolved O2 with 30a-c at pH 7.4 appears to be strikingly different from that of 5, 7-DHT, which undergoes autoxidation at pH 7.4 via the 4-hydroperoxy derivative 4 to the quinone 6. Thus, contrary to expectation and as judged by ultraviolet-visible spectroscopy, 30a undergoes autoxidation via the p-quinoneimine 31a to give the quinone 6 with loss of fluorine ion while 30b gives an unidentified colorless product(s) and 30c does not react with oxygen at pH 7.4.