[Nescafe]

Hi,

I'm working with an aniline and I'm at a step of my synthesis where I need to do a dialkylation to afford a dimethylated aniline product. Basically imagine an aniline and I'm doing reductive amination using excess formaldehyde (37% water) (10 eq), AcOH (2.5) and sodium cyano borohydride (4eq).

I'm getting horrible yields. The formaldehyde I'm using is four years old but I can't explain why I'm getting such poor yields. I add formaldehyde to a solution of my aniline in CH3CN, ACOH then NaCNBH3 and ACoH. I purify without any work up, usually there is a lot of starting aniline left.


Any advice would be appreciated!

Cheers,

Nescafé.

[discodermolide]

Perhaps you should get some fresh formalin. How long are you leaving the reaction for, 1 hour, 2 hours?

[Nescafe]

Perhaps you should get some fresh formalin. How long are you leaving the reaction for, 1 hour, 2 hours?

I ordered new formaldehyde in water from sigma today. First time I left it for 2 hours and it was bad. Second time for a day and it was worse... Can't understand why. I had more SM when I left it for a day than when I left it for 2 hrs

[discodermolide]

Of course you must form the imine in this reaction which is then reduced. Imine formation requires the loss of water from the hemi-aminal. This is an equilibrium process, therefore I would expect the presence of water to e detrimental to this reaction. You need to use a source of anhydrous formaldehyde.
Have you tried the direct alkylation?

[opsomath]

I knew I had a procedure where I had done direct alkylation of an aniline, it took me awhile to find it though. Here it is:

General Procedure for the Synthesis of Diallylaniline from Aniline. In a 50-mL round-bottom flask fitted with a reflux condenser and stir bar, 0.91 mL of aniline (9.8 mmol), 1.99 mL of allyl bromide (0.023 mol), and 1.06 g Na2CO3 (0.01 mol) were added to 32 mL of ethanol and 8 mL of H2O and refluxed overnight. The crude product was extracted with diethyl ether and concentrated, dried over anhydrous MgSO4, and distilled over potassium hydroxide to provide colorless diallylaniline (1.60 g, 9.3 mmol, 93%).

You might try this one rather than reductive amination, with MeI or even dimethyl sulfate in the place of allyl bromide. It was an easy and effective procedure in my hands.

[Nescafe]

Of course you must form the imine in this reaction which is then reduced. Imine formation requires the loss of water from the hemi-aminal. This is an equilibrium process, therefore I would expect the presence of water to e detrimental to this reaction. You need to use a source of anhydrous formaldehyde.
Have you tried the direct alkylation?

New formalin and also using just AcOH as solvent worked! Thank you