In order to guide the synthetic process, we started a theoretical study of the mechanism of the Fischer indole synthesis, so we could gain a better understanding of the electronic factors that influence the course of the reaction.
Several members of the indole alkaloid familiy, flavopereirin and sempervirin among them, have shown antitumor activity. Since our drug-development efforts focus on the indoloquinolizinium moiety, recently we have become interested in synthesizing substituted tryptamines as intermediates for the synthesis of indoloquinolizinium analogues with enhanced antitumor activity.
Pedro de Alba S/N San Nicolas de los Garza, NL, 66400, MEXICOWe report preliminary results of our study of the mechanism of the Fischer Indolesynthesis for a later study on substituted tryptamines.
For the reader unfamiliar with the indoloquinolizinium skeleton, the following embedded structure illustrates the skeleton itself, as well as its basic naming scheme in rings A, B, C and D.
Despite our repeated attempts to guide the structure "downhill" to reach an energy well, the calculation of vibrational frequencies kept showing one imaginary frequency corresponding to the indolic nitrogen.
This may help explain why, although the Fischer indole synthesis can produce a variety of substituted indoles, we have not found reports of production of indole by this method.
So it may well be that, in the resulting indole structures, the lone pair on the nitrogen fails to extend the aromatic system to the five-membered ring, and ring strain produces the increased energy.