[asa029]

Hello everyone,

I'm working on a reaction where an aromatic amine is to be N-alkylated through a nucleophilic attack to an alkyl halide. The reaction is conducted in refluxing THF.

When the alkyl halide is methyl iodine, the product is formed in good yields in 1-2 hours. However, iso-propyl bromide does not give any product, even after a day. This is probably due to elimination taking place in stead of the desired substitution.

Does anyone have any ideas on how to tune the reaction conditions in favour of substitution. I know solvent and temperature could be important, but are there any other variables that I should consider?

[discodermolide]

Hello everyone,

I'm working on a reaction where an aromatic amine is to be N-alkylated through a nucleophilic attack to an alkyl halide. The reaction is conducted in refluxing THF.

When the alkyl halide is methyl iodine, the product is formed in good yields in 1-2 hours. However, iso-propyl bromide does not give any product, even after a day. This is probably due to elimination taking place in stead of the desired substitution.

Does anyone have any ideas on how to tune the reaction conditions in favour of substitution. I know solvent and temperature could be important, but are there any other variables that I should consider?

Aromatic amines i.e. anilines are a bit less reactive and isopropyl bromide may be a bit sterically crowded for your reaction.
You could try acetone and a reductive amination.

[Dan]

I would also try reductive amination of acetone.

You could also reverse the functionality on the coupling partners and do a Buchald-Hartwig amination, though this may require a more drastic redesign of your synthesis, depending on how advanced your aniline intermediate is.

Is there a particular reason you don't want to proceed with the alkyl iodide even though it works well?

[asa029]

I would also try reductive amination of acetone.

You could also reverse the functionality on the coupling partners and do a Buchald-Hartwig amination, though this may require a more drastic redesign of your synthesis, depending on how advanced your aniline intermediate is.

Is there a particular reason you don't want to proceed with the alkyl iodide even though it works well?

Buchwald-Hartwig is not an option for this synthesis. I explored it earlier, but the reaction did not give the desired products.

The amine is not an aniline, but a heavily substituted imidazole.

I proceed with the N-methyl derivative, but I also want to produce a small library where the alkyl-chain gradually becomes more sterically hindered. That is why I want the iso-propyl substituent introduced:D

[discodermolide]

I would also try reductive amination of acetone.

You could also reverse the functionality on the coupling partners and do a Buchald-Hartwig amination, though this may require a more drastic redesign of your synthesis, depending on how advanced your aniline intermediate is.

Is there a particular reason you don't want to proceed with the alkyl iodide even though it works well?

Buchwald-Hartwig is not an option for this synthesis. I explored it earlier, but the reaction did not give the desired products.

The amine is not an aniline, but a heavily substituted imidazole.

I proceed with the N-methyl derivative, but I also want to produce a small library where the alkyl-chain gradually becomes more sterically hindered. That is why I want the iso-propyl substituent introduced:D

I don't know which substituents you have, you could try KHMDS and the iso-propyl iodide as an electrophile, as already suggested.
But this is not really conjusive to easily forming a small library. But it may give you the desired compound.

[milo2112]

You could try running the reaction in DMF or NMP with some added KI. Secondary alkyl halides really like to eliminate if if possible, but you may be able to squeeze some product out through the use of a highly polar aprotic solvent.

[Babcock_Hall]

We alkylate derivatives of nicotinamide with primary alkyl iodides in acetonitrile.  I seem to recall similar reactions being performed in THF.  I don't have any experience with secondary alkyl iodides, however.