[Mobius1988]

Ive recently carried out a reaction to form a one carbon primary alcohol by firstly conducting a lithium halogen exchange, followed by reaction with DMF. Finally I added NaBH4 to give me the methanol fragment on my molecule. Im having a little trouble with understanding the mechanism and why i dont just get a reductive amination instead.

 My intial assumption was that I would kick out NMe₂ to form the carbonyl and then do a standard NaBH₄ reduction. However surely the NMe₂ would then go on to react with the aldehyde to form an imine instead? I found this site which explains that the resulting lithium salt is stable until you do an aqueous work up:

http://www.alsnotebook.com/formylation.html

However now I am wondering how the NaBH₄ would go about reducing that species without the aqueous work up in between? Also when you do an aqueous work up to try and get the aldehyde why do you not just get a reductive amination with the HNMe₂ or form an acetal?

[OC pro]

I have done this recently. Works quite well. First deprotonation with LDA (2-methylpyridine, -70°C to -50°C), then quenching with excess DMF (5equiv.) at -78°C, slowly warming to room temperature, then addition of methanol (proton source!) and 1equiv. of NaBH4. Got a decent yield of 66%.

[Mobius1988]

I got a yield of 20% (which wasnt that much worse than the paper i followed who only got 30%). But i think this was because each step didnt quite go to completion and when I added the next reagent it caused a lot of side reactions.

So from what youre saying about the methanol I'm assuming that when you add the methanol it acts as the proton source to form the aldehyde and amine byproduct from the lithium coordinated species depicted in the diagram in the above link? Then the aldehyde is reduced by the NaBH₄, not the intermediate?

How much methanol did you add? Ive seen before that NaBH₄ is often used in an alcohol solvent but does this not just quench the reducing agent and release hydrogen before it even reacts with your substrate?

[OC pro]

If you would reduce the imine intermediate you would get the amine! This is actually done in reductive aminations. The amount of methanol should be more than DMF. Add 50 equivalents and then you´re on the safe side.
You can follow also the formylation (TLC, GC-MS, LC-MS). Why putting the reagents into the flask without checking the reaction progress?

[Mobius1988]

Im sorry but youve confused me, as far as im aware there is no imine intermediate in this reaction? I was under the impression the lithiated species reacts with the carbonyl in DMF and then the methanol will remove the amine to give you your aldehyde, which is then reduced by NaBH₄?

I was monitoring the reaction by LC-MS but what appeared to be 95% complete reactions in the first couple of LC-MS's turned out to be significantly less complete in the final LC-MS i took. No idea why.

Im conducting the reaction again tomorrow and will leave it for extra time and warm the mixture towards room temperature at each stage to make sure its complete.

[OC pro]

Yeah of course no imine intermediate. You should not only trust LC-MS. Develop a good old TLC in addition.

[Mobius1988]

Ok, im with you now. Thanks for the help, much appreciated.