[superg]

Hi,

i have a protected propargyl alcohol (with TiPS as protecting group) and i would like to protect the alcohol with a methyl (to for a methoxy group)

i'm hesitating between BuLi/MeI and KH/MeI... does it makes any difference? KH is not nucleophilic, so could be better...

does anyone have any experience/thoughts about this? mostly about equivalent of reagents, and order of introduction if KH is used...

thanks

[Doc Oc]

Some things you should think about:

1) What's wrong with the TIPS protection?  The methyl will be FAR more difficult to remove.
2) n-BuLi is a strong enough base to deprotonate a terminal alkyne, although the alcohol is several orders of magnitude more acidic so that will almost certainly go first.  Nonetheless, it's a consideration.
3) Are you using dry KH or a dispersion in mineral oil?  Dry KH is pyrophoric and should be used with care.

That being said, every time I've done methylation Et₃N was a good enough base to work and I don't see any reason it wouldn't work on your compound as well.

[OC pro]

@ J-bone: Just compare the pKa values and you will see that Et3N is not a suitable base for the deprotection of alcohols. TIPS (and TPS) is by the way very stable and sometimes not so easy to cleave.

@superg: I don´t see problems with the 1.0equiv. BuLi/ 1.5equiv. MeI couple (THF as solvent), deprotonation at 0°C and then quench with MeI. Instead you can also use 1.0equiv. NaH (better to handle than KH) and small excess of MeI in DMF.

[Doc Oc]

I'm aware that Et₃N is a weak base, and as I said, I've done methylations using this as the base without incident.  Under these conditions the alcohol will attack first and the base deprotonates second, not vice versa.

[superg]

sorry about the imprecision: the TiPS is protecting the triple bond (on terminal carbon), that's on the alcool that i want to put the methyl.

i ruled out trietylamine since the start, as on similar compound it deprotonate the alcool first and then get added on the terminal carbon with loss of the alkoxyde (TMS-O in that case)... looks like a base which have an inert conjugate acid (butane for BuLI, H2 for H-).

i think i'll go for BuLi, that was my primer idea.