So, if I have a Compound, for example Tryptamine,
and want to Methylate at the N-position.
Is it possible to calculate how likely it is to double-methylate the primary Anime instead of the secondary amine in the indole Ring?
[Edited on 10-9-2018 by Amoled]Loptr - 10-9-2018 at 07:24
I think it depends on how you are alkylating the nitrogen. Methyl iodide? Formaldehyde/NaCNBH4? Etc, etc.
Methyl iodide would probably give you a tertiary amine. The indole nitrogen is reasonably inert to electrophilic alkylating agents.Heptylene - 10-9-2018 at 13:29
Interesting question. This depends on a lot of factors like choice of solvent, reagents, temperature, concentrations, etc. I don't know about
calculating, but there are probably articles on that topic that give an idea of what will most likely happen under what conditions. Selectivity is the
keyword here.
Interesting example too. I wonder why you would want to methylate tryptamine at only one of the nitrogens. Hmm...clearly_not_atara - 10-9-2018 at 15:46
Loptr: I think methyl iodide would give a quaternary ammonium.
Amoled: The reactivity is determined by the nucleophilicity:
However, the nucleophilicity varies with the acidity of the solution containing a molecule. In a strongly basic solution, the indole is deprotonated,
and when that happens it will be more nucleophilic than the amine. Under most normal conditions, the amine is much more nucleophilic than the indole,
and will be alkylated three times before the indole is alkylated.zed - 17-9-2018 at 18:04
Amoled,
Generally speaking, the hydrogen located on the 1-position of the indole ring, isn't very easily substituted.
N-Methylation or N-Dimethylation of tryptamine, by conventional means, isn't generally easily accomplished either.
Indoles are fussy, and they self-destruct, when they are displeased by reaction conditions.
So..... Alternate approaches are often employed.
Notably, N-Dimethylation via reaction with formaldehyde, and simultaneous reduction of the resultant imines with Sodium Cyanoborohydride.
Now, if you come up with a better method, let us all know.
Chemists all over the planet, have been pondering this problem for the last hundred years or so.
[Edited on 18-9-2018 by zed]nimgoldman - 18-9-2018 at 14:17
Have you considered sodium cyanoborohydride in methanol?
