First of all i don't understand the part " was reduced from a methyl-ether " if it was a phenol-methyl ether (Anisol-like compound) then it should have been a hydrolysis. For the O- TBMDS Phenol synthesis i would go with a different approach: 1.1 -1.3 eq. of NaH in THF (if starting compound is soluble in THF (should be)) depending on the quality of THF add your phenol dissolved in THF over 10 min --> stir at rt for 30 min, cool to 0°C drip in XSiCl over ~ 30 min --> check TLC after 10 min.

This should reduce any interferences of additional organics like imidazole/Et3N during TLC.

And yes O-Silyl compounds (esp. O-TMS) are known to easily decompose on silica gel columns (slightly acidic environment + some water ).

Deactivating with 1- 5% Et3N helps in some cases.

Hope this helps

Hi, literally just did this exact reaction.

First thing: Silylations in DCM are drastically slower than in polar aprotic solvents like DMF. If you are going to do silylation in DCM, let it go overnight.

Secondly, make sure DCM is dry. Shake and distill from CaCl2 and store over molecular sieves under nitrogen or argon gas.

Also you say triethylamine or imidazole? Most people use imidazole because it forms reactive silylimidazolium cation which is attacked by ROH. Triethylamine can maybe do the same but its hindered and the formation of triethylamine-silyl complex might be slow. most people use reactive nitrogen-containing species such as imidazole, pyridine, or DMAP. I wouldnt recommend triethylamine. Unless you are using it to act as proton scavenger. Regardless you should have imidazole.

If you want silylation to be done in less than 2 h, run in dry DMF. Otherwise just do what I did and let it go in DCM overnight.

Greg Petruncio So I did let it go O/N in DCM; the TLC ended up looking exactly like the night before. Definitely dry DCM too - we have a solvent system that does that for us. Haven't tried DMF though; might try it if stuff doesn't go right.

I've now done this in both triethylamine and imidazole; I lost a bit of material with imidazole @ the crude stage before purification.

Fabian Rüger Yes - it's an anisol-like compound (appended to a lactone as well). Thanks for the advice - I don't think we'll be using NaH - just imidazole / Et3N.

Oh i see you are doing a phenol derivative. What other functinalities are on your phenol?

Are you using TBSCl? If you are having trouble with that, TBSOTf might be better.