[morten925]

Hello,

I want to synthesize (3-indolyl)acetic acid from gramine, i.e. a tertiary amine group to a carboxylic acid group in 3 steps. I was thinking of starting with the conversion of the tertiary amine group to a quaternary ammonium cation and then go on to the elimination of the salt to to an alkene via a Hofmann elimination. With heat, KMnO₄, OH^- and acid it should be possible to break the alkene into a carboxylic acid + formaldehyde. What I did not take into consideration is that the nitrogen in (3-indolyl)acetic acid is bonded to a CH₂ that's bonded directly to an aromatic 5-membered ring, hence making it impossible to carry out the Hofmann elimination. Now, without success, I have discovered nothing in textbook and online papers that illuminates this reactivity.

[clarkstill]

Your synthetic route won't work anyway, the product will be one carbon short once you do the oxidative cleavage.

It may not be a classical Hofmann type elimination (i.e. an E2) but you can definitely eliminate the ammonium salt and do substitution reactions, with neighbouring group participation from the indole nitrogen lone pair to stabilize the intermediate Sn1 carbocation, see here:

https://en.wikipedia.org/wiki/Gramine

So what you'd need is a nucleophilic reagent to ultimately form the acid, i.e. the synthon "CO2H-". What might fit the bill?

[morten925]

Unfortunately nothing that meets the requirement for a 3-step synthesis, but you could use ^-CN as a nucleophilic reagent and then hydrolyze it to ultimately form the acid. But that is a 4-step synthesis. Am I wrong?

[k1mng]

^-CN addition sounds great! Apparently it's not necessary to do a classical Hoffman elimination following making the trimethylammonium salt of gramine, and you can throw in your nucleophile to get your one-carbon homologated product from the trimethylammonium salt.

So I count 3-steps including the subsequent hydrolysis of the nitrile group, unless I'm missing something.

[morten925]

Thank you, the link to the wikipedia site of gramine shows the elimination but in the synthesis of (3-indolyl)acetic acid this is apparently not necessary.