[Babcock_Hall]

https://pubs.acs.org/doi/pdf/10.1021/i360042a003. 1972 "Silylation of organic chemicals" by Charles Roth
https://www.intechopen.com/books/gas-chromatography-derivatization-sample-preparation-application/derivatization-methods-in-gc-and-gc-ms. 2017

One of our synthetic targets this summer requires us to use silylation of a derivative of glucose, and we will initially use the tert-butyldimethylsilyl group, as per wildfyr's suggestion.  We will need to deprotect in the presence of a vinyl sulfone.   In the past I used to use cesium fluoride to deprotect a primary alcohol that was trimethylsilylated; in this case I was planning to use TBAF.  I have done a little bit of reading in Greene and Wuts's book on protecting groups, and that raised a few questions.  I have turned up one or two old papers, and one open access chapter, the second link above.  Perhaps some additional background reading would help us.  Would anyone care to recommend a good review article or book chapter?

[rolnor]

If your compound is sensitive, you should be ware that the reaction mixture becomes very alkaline when you desilylate with the reagents you suggest, if you want to avoid this you can use pyridine-HF or similar acidic fluoride source.

[Babcock_Hall]

That's a good point. When I worked with CsF, it was dissolved in methanol, and our product was a primary alcohol.  If methanol became deprotonated (presumably an equilibrium mixture of alcohols and alkoxide ions was present), it would produce a decent nucleophile.  That might cause problems.

[Babcock_Hall]

I have not previously encountered pyridine•HF, but I just looked it up and saw it referred to as the Olah reagent.  I trust that there is not a problem with toxicity.

[rolnor]

Its really bad to get on skin, painfull burns, pain can remain for long time. I think there is also triethylamine trihydrofluoride that can be used, this is probably less nasty I would guess.

[Babcock_Hall]

Halmos T et al., "STUDIES OF THE SELECTIVE SILYLATION OF METHYL α-D-AND β-D- ALDOHEXOPYROSIDES: STABILITY OF THE PARTIALLY PROTECTED DERIVATIVES IN POLAR SOLVENTS". Carbohydrate Research 170 1987 57-69.

We would like to add four TBDMS groups to an aromatic glucoside.  We have an aldehyde group on the aromatic ring.  The paper above was mainly concerned with partially silylated derivatives of four methyl glycosides, two glucose, two galactose, and one mannose derivative.  Under their condition A (2 mole of imidazole per mole of TBDMSCl in DMF; 24 hours at room temperature), they varied the ratio of TBDMSCl from 2.2 to 3.2 to 4.3 equivalents.  When they used 4.3 equivalents, they saw a variable amount of tetrasilylated product, from undetected (apparently both anomers of methyl galactoside) to 5% (the alpha forms of methyl glucopyranoside and methyl mannopyranoside) to 38% (methyl-β-D-glucopyranoside).

This leads to some questions.  The first is whether our change from methyl to an aromatic group at C-1 (the anomeric position) will cause the reaction to speed up or slow down (my prediction is that it will not make much difference either way).  The second is how to increase the yield of the tetrasilylated product.  There are only a few non-patent references I have found so far on the use of TBDMSCl to react with glucosides, but I may have narrowed my search too much.  IIRC I focused on TBDMSCl/imidazole-utilizing reactions, because these are the reagents that we purchased.

Two more things.  I found a paper (see below) which turned glycosides into trimethylsilyl derivatives, using bis(trimethylsilyl)trifluoroacetamide with 1% TMSCl in pyridine at 60 °C for 30 minutes.  It is fair point that the conditions are different, but could it be that the greater bulk of the tert-butyldimethylsilyl group makes it difficult to obtain fully silylated material?

Finally, is  N-methyl-N-(tert-butyldimethylsilyl)-trifluoroacetamide a stronger donor of tert-butyldimethylsilyl groups than the silyl chloride?  I will do a search for recipes in the next few days.

Isidorov, VA Journal of Chromatography A, 1521 (2017) 161–166.  http://dx.doi.org/10.1016/j.chroma.2017.09.033 

[Babcock_Hall]

In the 1987 paper that I cited, their Method B used catalytic DMAP (8% by mole), along with 2 equivalents of TBDMSCl, and triethylamine was the base.  Their method A used a variable number of equivalents of TBDMSCl.  I have not yet compared Methods A and B at the same mole ratio of TBDMSCl to methylglycopyranoside.

I also wanted to draw attention to the failure to observe any tetra-silylation with methyl galactopyranosides as substrates.  The three substituents on C3 (-OH), C4(-OH), and C5(-CH₂OH) are all on the same side of the ring, in contrast to glucopyranosides, where the substituent at C4 is on the opposite side of the ring.  This is consistent with a steric problem, although I would hesitate to call it strong evidence.

[rolnor]

You can use TBDSOTf its more powerfull. When you want to protect this many groups in close proximity it does not seem ideal to chose such a large PG because if steric bulk. Have you thought of other PG-s? I think SEM can be similar deprotected with fluoride and has similar stability but much less bulk.
M https://pubchem.ncbi.nlm.nih.gov/compound/2-_Trimethylsilyl_ethoxymethyl-chloride

[Babcock_Hall]

One possibility is to add DMAP into the standard conditions (TBDMSCl/imidazole).  However, I only found one published example, and the results were not impressive.  I did another search, and I found several examples where TBDMS-trifluoromethanesulfonate was used in similar reactions.
EDT
Another possibility is to take our chances with trimethylsilyl as the protecting group.

[rolnor]

If you want to do stuff like chromatography or wet workup the TMS will not be stable.

[Babcock_Hall]

Zelenka, Karel et al., Chemistry - A European Journal, 17(49), 13743-13753, S13743/1-S13743/45; 2011.  https://doi.org/10.1002/chem.201101163

Good point about chromatography.  Concerning DMAP/TBDMSCl/imidazole/DMF, there is one paper which used these conditions at 50 °C for 5 days.  The substrate was a steroid derivative of glucose, and the yield was 10%.  I could live with 38%, which is what the 1987 paper obtained with slightly different conditions.
EDT
Kaburagi Y, Kishi Y, "Operationally Simple and Efficient Workup Procedure for TBAF-Mediated Desilylation: Application to Halichondrin Synthesis" https://pubs.acs.org/doi/pdf/10.1021/ol063113h
I found a paper on deprotection using Dowex-50 and calcium carbonate that might be useful.  "For the cases where deprotected products have a high water solubility, the protocol of aqueous-phase extraction is not ideal. Despite this concern, very limited TBAF workup methods are known to avoid an aqueous-phase extraction. Thus, a TBAF workup with no use of aqueous-phase extraction is potentially useful."
This paper adds TBDMS groups to methyl-α-glucopyranoside using TBDMSCl, pyridine, and AgNO₃.  It also works for methyl-β-galactopyranoside.  Silver nitrate is not exactly inexpensive, but this method has yields greater than 70%.

[rolnor]

I strongly suggest you change PG-strategy, the SEM can be introduced with mild conditions, TEA/DCM I believe. If you can see so much problem  at this early stage its really not good.

[Babcock_Hall]

I strongly suggest you change PG-strategy, the SEM can be introduced with mild conditions, TEA/DCM I believe. If you can see so much problem  at this early stage its really not good.

I will look at SEM, but I wonder whether or not we cross-posted.  The silver nitrate protocol from the Kishi lab looks attractive, unless silver nitrate is incompatible with the presence of an aromatic aldehyde.  Based on Tollens chemistry, I suspect that silver ion would oxidize the aldehyde, unfortunately.  However, the desilylation methodology in this paper may still be applicable to our project.

[rolnor]

TBDMSOTf is probably more efficient then TBDSCl and silver nitrate. For workup I suggest you filter through a short column with RP-18 silica, maybe eluting with MeOH/H2O say 2:1. The Q-salts from TBAF will stick hard to the gel. If you use pyridine-HF you can perhaps just evaporate and apply som vacuum. The compound you are making is so polar  that it is likely you need RP-silica for purification, this requires some training. You can also run RP-TLC for monitoring, again this is so different from straight-phase silica so it will be extra work. If you use prep-HPLC for purification its easier.

[Babcock_Hall]

One source of general information that I found useful is the fourth edition of Greene and Wuts' book on protecting groups.  They have three useful tables near p. 190 giving the lability of various silyl groups to acidic and basic conditions, and to the presence of TBAF in THF.  TBDMS is much less labile to base than TMS is, although both are quite labile to 1% HCl.  There is some discussion of how to reduce the water content of TBAF.  I think that there might be an error in one entry of the second.  There is a long-chain alcohol protected with TBDMS, and its half life in the presence of Bu₄NF is given as 140 hours.