[Guitarmaniac86]

I have a synthesis problem I am working on. I am protecting a diol that contains a ketone with TBDPS-Cl because I need to convert the ketone to a thione. The literature procedure I am following carries the reaction out in dry DCM however the diol is insoluble in it so I am using DMF. When I calculate the mass of product I should get it is significantly more than I am able to obtain.

The reaction is monitored by TLC and shows completion by about 4 hours and it is worked up as follows: The reaction crude has an equal volume of chloroform added and this is transferred to a separating funnel containing 1M LiCl solution. The organic layer is removed and the LiCl solution (the aqueous phase) is washed with chloroform three times (3x reaction volume). The chloroform is vac'd off and 100 ml toluene is added and vac'd off to azeotrope off any remaining DMF.I suspect the product is stuck in this aqueous phase but TLC'ing the aqueous phase shows nothing, however, is it possible for the lithium to associate with my ketone and pull it into the aqueous phase along with the DMF?

I only ask because of this observation: When I column the crude, I get 600mg of my product and 1g of the TBDPS-OH out pure. This means I have lost 2g of the TBDPS-Cl somewhere. Assuming the 2g of TBDPS reacted with the starting material I am missing about 1.4g of product.

Due to confidentiality reasons I am unable to disclose structures but the calculations for working out yields etc are correct and there seems to be a lot of product missing. Re-extraction of the aqueous phase shows no product and the column was run to completion with TLC showing perfect separation of all spots with no co spots. Also the column was flushed with 1:1 EtOAC:Pet ether and 90:10 EtOAc:MeOH.

I am tempted to redo the reaction and wash with 10x reaction volume of just water and then azeotrope off the DMF with toluene after I extract with chloroform.

[OC pro]

Have run hundreds of rxns with silyl protecting groups. Loved them! Do you have both alcohols as secondarys or is it a prim and a sec?
How are your conditions? I think you have missed the base! The normal protocol would be like 1.2 equiv. of TBDPSCl, 2.4equiv. imidazole (mandatory!), DMF, rt. Normally this rxn is very fast since imidazole is working as a catalyst.

[Guitarmaniac86]

Oh they are both primary alcohols and the conditions are:

1 equiv diol containing ketone
2 equiv TBDPS-Cl
3 equiv imidazole

all in DMF reacted at rt for 4-5 hrs or until completion. I am not getting the yields I am expecting though and TLC shows completion

[Dan]

Is the product you isolate definitely the bis(silyl ether) by MNR and/or MS? i.e. is it possible that you only got protection of one of the alcohols, hence a lower mass than expected?

I just ask because TBDPS is quite a sterically demanding group.

Also check the very early fractions in your column to make sure some of it didn't get dragged through with the load solvent.

Your prep looks fine, and I doubt the product will go into the aqueous layer to a significant extent.

[Guitarmaniac86]

Hi Dan, thanks for the response.

NMR shows pure di-silylated product but I am currently waiting on MS.

I have checked the early fractions and the solvent waste from when I load the column (I always push out half to one column volume before I collect fractions) and that shows nothing after rotovaping off the solvents and taking a TLC of anything that maybe there.

[Guitarmaniac86]

Sorry for the double post however I did not want to make a new thread regarding the same reaction.

I went over the lab book calculations and it turns out I was using an excess of TBDPS-Cl and as such when calculating yields I was way off so the reaction did go to completion. However, the product is a solid after I purify via column but I would rather recrystallise from the crude.

The crude once the DMF is washed off is a brown/gold thick oily oil and I know the product is no that soluble in ACN, however I just cant get this thing to crystallise. I have tried the following:

-Pure ACN
-Pure Et₂O
-CHCl₃/petroleum ether
-Pure EtOAc
-Pure EtOH

But non of these systems seems to allow crystalisation. The crude NMR shows a lot of DMF is still present and I have tried azeotoping it off with toluene, and then azeotroping with EtOAc then with CHCl₃ and then putting it on high vac for a few hours but DMF is still there so I am wondering if the DMF can prevent crystallisation from occurring.

Edit: The structure is C₃₅H₄₂Si₂O₃ so its really non polar and I thought it would recrystalise from polar solvents but evidently not...

[Dan]

I'd recommend washing out the DMF, it is very difficult to get rid of it all under vacuum (at least in my hands).

Useful thread: http://www.chemicalforums.com/index.php?topic=60713

I would also wash out any excess imidazole with dilute HCl(aq).