[Reddart]

My goal is to alkylate a phenol that is ortho to a primary amine on a phenyl ring. I'd "like" to use a Mitsunobu reaction with a primary alcohol substrate, but am guessing the amine will compete with the phenol (or phenolate, if in base).

Is there a way to selectively protect the amine in the presence of the phenol? FWIW, there is an electron withdrawing group meta to the phenol and para to the amine. I'm looking through Green right now to see if there are amino protection schemes in the presence of a phenol.

[phth]

I would look into an acid mediated substitution of the substrate will tolerate that.  You could start from an azide+carboxylate, and transform it in situ to a isocyanate and in the presence of an alcohol will become a Cbz/Boc/Fmoc group.  Why start from a phenol? If you used a cross coupling reaction you could accomplish the alkylation in 1 step and it would tolerate the amine. .

[zarhym]

I would try another approach like hydrogenation of nitro group to solve the problem. Phenol will oberviously survive the hydrogenation conduction such as H2/Pd.

[TheUnassuming]

I would think the pka difference between the phenol and amine would be different enough to favor reaction at the phenol rather than the NH2.  That said, having a free phenylamine will pose a problem with mitsunobu reactions for a different reason.  They have a tendency to form imine-phosphorane type structures during mitsunobu reactions when not protected and those can be a pain to "deprotect".

You could protect globally with boc or similar, then selectively deprotect the phenol.  I've done this with a phenylamine and alkyl-OH with good success before, but don't know how well it would work with a phenol.   

[zuriel]

You could protect globally with boc or similar, then selectively deprotect the phenol.  I've done this with a phenylamine and alkyl-OH with good success before, but don't know how well it would work with a phenol.

Can you give any further details/procedures for this? Looks like something that could really help me down the line! 

[TheUnassuming]

Of course!
I just globally protected with boc using stp, which typically gave the di-boc protected NH2 and hit my OH as well.  When you want your alcohol back you can hit it with excess NaOH or LiOH in MeOH/H2O which clips the carbonate to give back the alcohol and depending on the exact phenylamine usually clips one of the boc's there as well to give the mono-boc protected substrate. 

[TheUnassuming]

If your substrate can handle it you can sometimes use hydrazine to clip carbonates as well, but never got it to work cleanly on my compounds.

[Reddart]

It looks like the phenol is alkylating preferentially over the amine, with a little over alkylated product that is easily removed in a column. So far I haven't needed to protect.