[Guitarmaniac86]

I am coming to the end of my research for my Masters and I have been trying to synthesize several compounds to study the SAR of an inhibitor the research group I work in discovered. Without going into too much detail, I have 4-bromo-3-hydroxymethyl phenol which I need to protect so that I can use it in several palladium catalysed cross coupling reactions.

I tried MOM but this made the benzene ring too electron rich and coupling suffered greatly, in fact, barely any product was formed (it was too electron rich to undergo oxidative insertion). I cant acetylate because it is base labile so I have tried to benzoylate.

First I tried:

1 equivalent 4-bromo-3-hydroxymethyl phenol, 2 equivalents benzoyl chloride and 2 equivalents DMAP in THF and 35 equivalents TEA  at room temperature but it didnt work. Then I tried the same reaction, instead I heated to 60 degrees for 2 days. No product had formed.

I tried again this time in DMF, but instead of TEA I used 6 equivalents NaH at 0 degrees warmed to room temperature and added benzoyl chloride once the fizzing from NaH had stopped. This too didnt work.

So next I added the NaH at room temperature, waited an hour and added the benzoyl chloride with the DMAP and left it for a few days. Again no product had formed. Crude GC-MS showed only starting materials. I purified via column each time just in case but I only separated the starting materials.

Any help is appreciated. If you suggest a protecting group for the alcohol, I need a group that will give me an electron deficient benzene ring because these types of bezene rings undergo cross coupling with excellent yields (already tested electron deficient beneze rings for a different SAR with the same coupling reaction and it worked).

[orgopete]

Two equivalent of DMAP? Everything sounds like overkill. Check your reagents. Try a lit prep.

[nox]

If you want something really electron-withdrawing but not too base labile or prone to oxidative addition you could try making the trifluoroacetyl ester by reacting the hydroxymethyl group with trifluoroacetic anhydride.

[Guitarmaniac86]

Two equivalent of DMAP? Everything sounds like overkill. Check your reagents. Try a lit prep.

The reagents were bought new in July but I will check them anyway.

Everything I posted were modifications on literature preps. I performed a scifinder reaction search for my starting material that came up with no hits so I found two literature preparations: one for phenolic benzoylation and one for benzyl alcohol benzoylation. They were practically the same, both used 1 equivalent of the alcohol, 15 equivalents of TEA and 1 equivalent of DMAP in THF. I doubled the equivalents because I had double the hydroxy groups. Could this be where I have gone wrong?

(Every prep has been doubled from the literature prep, including preps using NaH).

If you want something really electron-withdrawing but not too base labile or prone to oxidative addition you could try making the trifluoroacetyl ester by reacting the hydroxymethyl group with trifluoroacetic anhydride.

I never thought of that, I shall try it!

[willug]

Do you know what the DMAP is for? I think if you talk about 'doubling the equivalents' of that in a viva you might be in trouble!

[Guitarmaniac86]

Do you know what the DMAP is for? I think if you talk about 'doubling the equivalents' of that in a viva you might be in trouble!

It catalyses the reaction between benzoyl chloride and the alcohol. It forms an intermediate that weakens the H-O bond of the alcohol, allowing the lone pair of the oxygen to attack the acyl chloride carbon. As this occurs, the DMAP becomes protonated and the TEA depronates DMAP to reform the catalyst.. I think. I am not 100% sure. I know its a nucleophilic catalyst so I may have it ass backwards what I wrote.

(Yeah I got it wrong, the DMAP attack the carbonyl carbon forming an adduct that allows the alcohol to attack, the carbonyl carbon displacing the DMAP. TEA then deprotonates the alcohol forming the product).

[willug]

So do you think it's needed in stoichiometric quantites? I think that was what orgopete was getting at...

[Guitarmaniac86]

So do you think it's needed in stoichiometric quantites? I think that was what orgopete was getting at...

I was suspicious of the literature preparations because when I have used DMAP in the past for other reactions, I typically used 10-20% DMAP, sometimes as low as 1-2%. I may need to try it this way and see. I didnt think I needed stoichiometric amounts since it is a catalyst after all.