[stimulusartifact]

Hey all - I'm just starting out with chemistry, and I have tried to think this one through a bit ... can anyone offer any help?

I am trying to completely alkylate an aniline with methylbromoacetate, but I must do so with several phenolic OH's elsewhere in my molecule.  Phenolic OH's are quite acidic, and I do not want to alkylate them.  On the other hand, I have a relatively small amount of material, and don't want a costly protection-deprotection round.

I was thinking to protect the phenols in-situ with 0.95 equivalents of t-butyldimethylsilyl chloride ...  Is this what the wise one would do?  And if so, what conditions would be sufficient to deprotect TBDMS protected phenols that I could do in the work-up (to deprotect with confidence)?

Similar N-alkylations generally proceed in the 12-16 hour ball-park in acetonitrile reflux, or dmf 100 degrees.


Any advice & principled reasoning would be awesome since I am just starting out!

Thanks!

[Custos]

I'd give it a shot without protecting, under neutral conditions. The aniline nitrogen will be more nucleophilic then the phenolic oxygens and bromoacetate is a pretty good electrophile. Try using just one equivalent of bromoacetate at low temp (ice bath) and let it warm to room temp overnight. Follow with tlc to see if the alkylation is progressing and if not you could heat then.

[barcrphd]

I'd give it a shot without protecting, under neutral conditions. The aniline nitrogen will be more nucleophilic then the phenolic oxygens and bromoacetate is a pretty good electrophile. Try using just one equivalent of bromoacetate at low temp (ice bath) and let it warm to room temp overnight. Follow with tlc to see if the alkylation is progressing and if not you could heat then.

first of all can the reaction proceed without a base? in my experience alkylation takes place at phenolic oxygen as well, if the same is not protected. even halides like 1,3-dibromopropane reacts with phenol in presence of weak base. so activated halides like methyl bromoacetate should definitely react with phenols.
and another doubt, how can a tlc be useful in knowing whether the alkylation is proceeding in the right direction ( in this case the amine and not phenol).

[Custos]

I think O-alkylation is a definite possibility to keep an eye out for. Under basic conditions the phenol would be deprotonated and ArO^- is a stronger nucleophile than ArNH₂. Under very strongly basic conditions (eg, 2 equivs of BuLi) both the phenol and aniline would be deprotonated and then the ArNH^- would be the strongest nucleophile.

However under neutral conditions both groups will be in their free acid state and then ArNH₂ is a better nucleophile than ArOH. At low temperature, one equivalent of the bromoacetate should go for the aniline first. Following by tlc will only show if some reaction has occurred. It will still be necessary to check where the alkylation went, but my bet would be on nitrogen.

Sometimes we reach for protecting groups too quickly when they may not be needed.

[wintermute]

hydrogene bromide formed in the course of alkylation will likely form salt with the starting aniline, and thus pasivate it from further alkylation. the addition of, say, pyridine could push the equilibrium towards free aniline.

[zq]

Why not add 1 eq triethylamine to deprotonate the amine (phenol should not).

[amancalledhorace]

Was curious how this one worked out?

/H

PS - another approach might have been to try reductive alkylation with glyoxylic acid ;-)

[alphahydroxy]

yeah - reductive amination might be a good way to go...