[Babcock_Hall]

We are attempting to remove a 4-methoxybenzyl protecting group from a carboxylic ester.  One protocol we found (Stelekatos, J. Chem. Soc. C, 1970, 964-967) uses anhydrous HCl in nitromethane.  I cannot find this reagent commercially, but someone suggested using nitromethane, acetyl chloride, and methanol or ethanol to produce it in situ.  Does anyone have any thoughts on this?  Thank you.

[fledarmus]

An interesting approach. I have used acetyl chloride to generate a 1M HCl solution in methanol, but I've never tried using acetyl chloride and methanol to generate a 1M solution in anything else.

I believe typically you bubble anhydrous HCl (purchased as a gas in a cylinder) through the nitromethane to generate the reagent.

[Babcock_Hall]

An interesting approach.  I suppose that one would have to titrate the solution, at least in an approximate way.  I doubt that it needs to be better than plus or minus 10% for our application.

[fledarmus]

If you route the outflow through an efficient condenser and add the HCl slowly enough that you aren't blowing out the nitromethane, you can get a fair approximation of the concentration from the increase in mass of the solution. Nitroethane, with a higher boiling point, is even better for this purpose. Titrations can be a little tricky since the nitromethane isn't extremely water soluble and you end up with an extra layer to deal with.

[orgopete]

That strikes me as my least favored method to cleave this protecting group. Could someone suggest an alternate from one of the protection-deprotection books and/or explain why the nitromethane method is preferred?

[fledarmus]

Ah - if you want alternative methods...

http://www.fpharm.uniba.sk/fileadmin/user_upload/admin/Acta_facultatis/Tomus_LII/04_-_Lukac__M._-_Smolarikova__E._-_Lacko__I._-_Devinsky__F.pdf

[orgopete]

I was looking for something a little less exhaustive, but it will do. If it were me, I'd try the 10% TFA in dichloromethane. Evaporate at the end et voila.

[Babcock_Hall]

I was looking for something a little less exhaustive, but it will do. If it were me, I'd try the 10% TFA in dichloromethane. Evaporate at the end et voila.

orgopete,

Thanks.  I have seen TFA and formic acid used in the literature, and we are exploring those reactions, party with the compound of interest and partly with a model ester.  What has puzzled me about these methods is that the products would seem to be the 4-MB esters of trifluoroacetic or formic acid, respectively.  Therefore, when one removes the volatiles, I wonder whether or not the equilibrium will be displaced by the removal of the volatile acid and shift back toward reactants.  Maybe I am thinking about it incorrectly.  I also wonder if this question should be posted in a separate thread.

BTW, our compound of interest has a pyridinium group, so I have not tried hydrogenation as a deprotection strategy.  I have not seen oxidation used to deprotect when 4-MB protects an ester (as opposed to an ether), but I will look through the article kindly cited by fledarmus.