[owk9688]

Does anyone have any general tips for dealing with 2 spots on a TLC that wont seperate and appear as 1? Its one spot regardless of what ratio of ethyl acetate/hexanes I use. Ive also tried DCM and Methanol with no luck at getting the spots to seperate. The NMR is showing a mix of TBS diprotected and TBS triprotected phloroglucinol and I need the diprotected. The compounds are both highly nonpolar and have an Rf of around .7 even in 10% ethyl acetate/Hexanes (around .3 in 6%)

Would a reverse phase column help the 2 spots seperate better or is there a different way to get past this issue?

Thanks for any help

[phth]

deprotonate the alcohol, and extract it after a column.  Other options are to lengthen, widen, or change solvent systems.  RP silica is a waste of money.

[MOTOBALL]

On silica gel plates, reduce the EtOAc % toget an Rf of about 0.1.
Run the plate 4 or5 times, allowing to dry thoroughly between each run.
I have found this technique to work very well for partially substituted polyols.

[Dan]

Try:

acetone/hexane
ether/hexane
EtOAc/toluene
acetone/toluene
ether/toluene
EtOAc/(1:1 hexane/toluene)
acetone/(1:1 hexane/toluene)
ether/(1:1 hexane/toluene)

[TheUnassuming]

DCM/hexane is a random one to add to that list.

Reverse phase generally doesn't work great with very non-polar compounds.

[wildfyr]

Which one do you want to obtain in the end? I'm guessing you tri-protected, then dropped a fluoride ion in really slowly or something to deprotected one, and are trying to get pure di protected in the end??

[owk9688]

Yes, I'm trying to isolate the diprotected. I'm going to try a bunch of different solvent systems suggested. The deprotonation sounds good but it would put my product as a salt in the aqueous layer which id then have to re-protonate without cleaving my TBS groups. I'll give that try if I can't find a system to separate the two products but it seems risky.

[phth]

TBS is big, and TMS is small.  TBS survives the column, and TMS doesn't.  TBS can come off in base, so I would cool the solution.  You should look on scifinder for a procedure involving A/B extraction in the presence of a TBS group.

[Babcock_Hall]

Have you tried alumina?  Just a thought.

@phth, What is an A/B extraction?

[Dan]

Personally, I expect that attempting to fully deprotonate the phenol and force it into the aqueous layer is very risky and unlikely to work, because even the salt may be too greasy to dissolve in water and the highly basic conditions required to do that will probably result in silyl hydrolysis - aryl silyl ethers have quite low stability in base - ArOTBS can be cleaved with LiOH in DMF, for example. That said, I could certainly be wrong and it is worth a shot if you have enough material.

Alumina is worth a shot, though usually in my experience the Rf on alumina is higher than on silica.

Can you use a less greasy protecting group that will make purification easier?

[wildfyr]

What about this guys:

Take your triphenol and SLLOOOWWLLY add 1 eq TMS-Cl in a dilute solution, then isolate the mono TMS (distillation perhaps? I'm sure someone has made it before and scifinder will find it). Then take this pdt, and add 2.1 eq of TBDMS-Cl (my preferred TBDMS protection conditions are DCM, 1 eq alcohol, 1.05 eq TBDMS-Cl, 2.1 eq imidazole, RT overnight. Has literally never failed. Ive also run it in THF, MeCN and DMF with no problems except the usual DMF extraction pain). Afterwards, do a water wash.

Boom, di-TBDMS protected triphenol. No column.

Maybe flash it with hexane through a small silica plug to push off TBDMS dimer that will form with the slight excess of TBDMS-Cl, then rinse your product through with DCM.

You might even be able to do this in one pot if you can get the first TMS protection done nicely.

I never thought TBDMS protection (which I did constantly for two years while working on SuFEx) would be so widely applicable on this forum.

[wildfyr]

Just a note I remembered this morning, I think phloroglucinol had crappy solubility in DCM when I made a tri-TBDMS protected version, so I ended up having to run it in hot MeCN. So be careful following my DCM example even for the mono-TMS version you might make. And for gods sake dry the phlorglucinol and solvents as best you can before you do any of this work.

[phth]

If you protect two of the alcohols as an acetal/ketal, then you only need 1 protecting group step.. a whole lot easier purification, and mixing, also.  The reason is that an intramolecular reaction is much faster than an intermolecular reaction.

What about this guys:

Take your triphenol and SLLOOOWWLLY add 1 eq TMS-Cl in a dilute solution, then isolate the mono TMS (distillation perhaps? I'm sure someone has made it before and scifinder will find it). Then take this pdt, and add 2.1 eq of TBDMS-Cl (my preferred TBDMS protection conditions are DCM, 1 eq alcohol, 1.05 eq TBDMS-Cl, 2.1 eq imidazole, RT overnight. Has literally never failed. Ive also run it in THF, MeCN and DMF with no problems except the usual DMF extraction pain). Afterwards, do a water wash.

Boom, di-TBDMS protected triphenol. No column.

Maybe flash it with hexane through a small silica plug to push off TBDMS dimer that will form with the slight excess of TBDMS-Cl, then rinse your product through with DCM.

You might even be able to do this in one pot if you can get the first TMS protection done nicely.

I never thought TBDMS protection (which I did constantly for two years while working on SuFEx) would be so widely applicable on this forum.

[Dan]

If you protect two of the alcohols as an acetal/ketal, then you only need 1 protecting group step.

But phloroglucinol is:



Initially when I saw "phloroglucinol" written, I assumed it was a sugar polyol and that an acetal/ketal strategy might be the answer, but it's not the case unfortunately.

[Dan]

What about this guys:

Take your triphenol and SLLOOOWWLLY add 1 eq TMS-Cl in a dilute solution, then isolate the mono TMS (distillation perhaps? I'm sure someone has made it before and scifinder will find it). Then take this pdt, and add 2.1 eq of TBDMS-Cl (my preferred TBDMS protection conditions are DCM, 1 eq alcohol, 1.05 eq TBDMS-Cl, 2.1 eq imidazole, RT overnight. Has literally never failed. Ive also run it in THF, MeCN and DMF with no problems except the usual DMF extraction pain). Afterwards, do a water wash.

Boom, di-TBDMS protected triphenol. No column.

Maybe flash it with hexane through a small silica plug to push off TBDMS dimer that will form with the slight excess of TBDMS-Cl, then rinse your product through with DCM.

You might even be able to do this in one pot if you can get the first TMS protection done nicely.

I never thought TBDMS protection (which I did constantly for two years while working on SuFEx) would be so widely applicable on this forum.

This strategy relies on the assumption that mono-TMS phloroglycinol is a lot less reactive than phloroglucinol. I would be surprised if the difference is that large. Maybe the strategy would work better with a more stable PG (orthogonal to TBS) that would survive chromatography, so even if the selectivity in the monoprotection step is low, at least the monoprotected product could be purified and isolated.

Presumably the next step in the synthesis is functionalisation of the OH of the diprotected triphenol. Another strategy would be to start from 3-hydroxy-5-iodophenol or a 3,5-dihydroxyphenylboronic acid derivative [though I have not checked commercial availability], whack on 2 x PG and then introduce the 3rd O substituent by cross coupling (i.e. Ullman or Chan-Lam type reaction). This could be a lot more direct than fiddling with a tricky PG pattern.