[voidSetup]

Hi all,

I'm looking to synthesize a fairly simple mesylate, and had a question about reaction conditions.  The two methods I've seen to make them:

1. Alcohol + methanesulfonyl chloride + TEA.  TEA is removed either by washing with 1M HCl or washing with NaHCO3 and removing by rotovapping.

2. Alcohol + methanesulfonic anhydride + pyridine + dimethylaminopyridine.

My question is what are the pros and cons of each route.  Methanesulfonic anhydride seems like it would be less toxic/dangerous to work with, and the reactions conditions are more mild although it takes longer.

Any thoughts would be appreciated.

[AlphaScent]

For simple mesylations, I just use methanesulfonyl chloride and pyridine as my scavenger.  Just wash with 1 N HCl and you are good. 

The method depends on the substrate. 

You are right, pyridine and the anhydride are less caustic.

[billnotgatez]

from
http://dwb4.unl.edu/Chem/CHEM869R/CHEM869RLinks/www.utmem.edu/allied/Solutions/Normality.html

For hydrochloric acid, 1 M HCl is equal to 1 N HCl

@AlphaScent
Just wondering why you posted
1 N HCl

[Dan]

My question is what are the pros and cons of each route.  Methanesulfonic anhydride seems like it would be less toxic/dangerous to work with, and the reactions conditions are more mild although it takes longer.

Another advantage of Ms₂O is that you don't need to keep an eye out for chloride displacement.

MsCl is much cheaper. Reactions are a lot slower with pyridine compared to TEA (I suspect there is a mechanism change - that sulfene is not formed with pyridine as it is with TEA).

[voidSetup]

My question is what are the pros and cons of each route.  Methanesulfonic anhydride seems like it would be less toxic/dangerous to work with, and the reactions conditions are more mild although it takes longer.

Another advantage of Ms₂O is that you don't need to keep an eye out for chloride displacement.

MsCl is much cheaper. Reactions are a lot slower with pyridine compared to TEA (I suspect there is a mechanism change - that sulfene is not formed with pyridine as it is with TEA).

Are you referring to chloride substituting the alcohol to give the alkyl chloride instead of the mesylate? 

I'm not too concerned with the cost.  If I go with the methanesulfonic anhydride, what would you recommend to clean up the pyridine/DMAP?  Wash with acid and then base, or azeotrope it with toluene?  I think my desired product should have a boiling point of ~300C.

[AlphaScent]

I use normality in the lab.  It has to do with reactivity more than just the amount in solution.  It is more applicable.

I would just use methanesulfonyl chloride in excess pyridine (3 equvelents). 

Monitor by TLC, quick and easy.

Wash with 1 N HCl until aqueous is acidic.  If your substrate has any reactivity towards acid (THP, ester, ect.) then wash with 0.1 N HCl.

Easy peazy.

[Dan]

My question is what are the pros and cons of each route.  Methanesulfonic anhydride seems like it would be less toxic/dangerous to work with, and the reactions conditions are more mild although it takes longer.

Another advantage of Ms₂O is that you don't need to keep an eye out for chloride displacement.

MsCl is much cheaper. Reactions are a lot slower with pyridine compared to TEA (I suspect there is a mechanism change - that sulfene is not formed with pyridine as it is with TEA).

Are you referring to chloride substituting the alcohol to give the alkyl chloride instead of the mesylate? 

Yes. It can be an issue with primary, benzylic or similarly activated mesylates.

If you're not bothered about the cost you could even triflate it (depending on the structure).

As for workup, I do an acid wash like AlphaScent suggests (again, depending on the structure).

[voidSetup]

I have one more question on this.  In some of the procedures I've seen, roughly ~20eq of pyridine is used.  Why is such an excess needed?  It's only there to regenerate the catalyst and act as a proton scavenger right?  Would 2-3eq not be sufficient?

[clarkstill]

Pyridine isn't just a proton scavenger in a mesylation reaction: if you can explain why mesylation and tosylation have different mechanisms, you should be able to explain why.

[AlphaScent]

The mechanisms are different??

[voidSetup]

I'm using methanesulfonic anhydride, DMAP, and pyridine.  I was just looking at the mechanism again and I can only think that pyridine deprotonates the leftover methanesulfonic acid (after esterification has occurred) so that the DMAP wouldn't extract that proton instead of acting as the catalyst.  I just don't see why it would be needed in such excess.

[orgopete]

Hint, look up 4-dimethylaminopyridine in Wikipedia. It is a catalyst. Twenty equivalents of pyridine are more than needed for the stoichiometry of the reaction. I'm guessing it is also the solvent.

[clarkstill]

The mechanisms are different??

Base-mediated elimination of MsCl generates a sulfene....