ABBREVIATED IBOGAINE CONGENERS - SYNTHESIS AND REACTIONS OF TROPAN-3-YL-2 AND 3-INDOLES - INVESTIGATION OF AN UNUSUAL ISOMERIZATION OF 2-SUBSTITUTED INDOLES USING COMPUTATIONAL AND SPECTROSCOPIC TECHNIQUES
Db. Repke et al., ABBREVIATED IBOGAINE CONGENERS - SYNTHESIS AND REACTIONS OF TROPAN-3-YL-2 AND 3-INDOLES - INVESTIGATION OF AN UNUSUAL ISOMERIZATION OF 2-SUBSTITUTED INDOLES USING COMPUTATIONAL AND SPECTROSCOPIC TECHNIQUES, Journal of organic chemistry, 59(8), 1994, pp. 2164-2171
The syntheses of several N-methyltropan-3-ylindoles, designed as conge
ners of ibogaine, are described. The synthetic approach to N-methyltro
pan-3-yl-2-indole revealed that the tropanyl 3'-center was quite sensi
tive to acid-catalyzed epimerization. The carbocyclic analog, N-methyl
-2-[bicyclo[3.2.1]-oct-3-anyl] indole, also underwent this rearrangeme
nt. However, N-methyltropan-3-yl-3-indole was insensitive to acid or b
ase, even under more vigorous conditions. This simple isomerization is
quite rare for 2-substituted indoles, especially for cases where the
center of reaction is not additionally activated, and normally only ta
kes place under extreme reaction conditions. The mechanism of this rea
ction was investigated using ab initio molecular orbital calculations,
NMR spectroscopy and deuterium labeling studies. These results indica
te that, in contrast to those previously obtained for more reactive 2-
substituted indoles, the reaction can best be explained using a simple
exchange mechanism involving the exocyclic enamine tautomer of the in
dole ring as an intermediate. The difference in reactivity is suggeste
d to arise from a decrease in the relative energy of the exocyclic ena
mine tautomer due to the presence of increased strain in the endo bicy
clic 2-substituent. The title compounds displayed modest pharmacologic
al activity in a variety of biological assays.