[Miep]

Hi,

I'm trying to demethylate the aromatic methyl ether from a compound having both an aromatic methoxy and butoxy group.  I don't want to loose the butoxy group, the compound also has an amide structure.  I tried BBr₃ in CH₂Cl₂, but the compound isn't stable in these conditions.  I don't find any information about this kind of selectivity, so maybe this isn't possible at all?  I don't need high yields...
If anybody has some experience with this, I would be glad to hear it!

Thanks!

[russellm72]

Hi,

I did a lot of BBr3 demethylations during my PhD and did them in DCM at -78 0C and some did contain amide linkages! I think you might struggle to differentiate between a butoxy and methoxy group cleavage but doing at a low temp and monitoring by LC-MS might see if you have any chance. Would it be easier to change your approach? Without knowing your scheme one can't say but could u protect your methoxy phenol as a PNB group instead which is easily removed by DDQ and your butoxy won't be touched?

R.

[movies]

Another set of conditions to try would be TMS-I.  I don't know that it would be any more selective though.

[lavoisier]

I'm doing medicinal chemistry, and for our derivatives we've found a method that is very mild but effective, at least for most of our methoxy and ethoxy aromatics.
Just mix your phenyl ether with 5 Eq pyridine hydrochloride and some water, say the same weight as Py.HCl, and heat it quite hard (normally 100°C or more).
Better if in a microwave reactor. And remember to use a pressure-resistant reactor!

If the butoxy you mention is a t-butoxy, though, I'm afraid you will have some trouble in differentiating the two ethers. You might check Greene's protective groups for selective deprotections.

[Miep]

Thanks everyone for the answers!

I'm doing medicinal chemistry, and for our derivatives we've found a method that is very mild but effective, at least for most of our methoxy and ethoxy aromatics.
Just mix your phenyl ether with 5 Eq pyridine hydrochloride and some water, say the same weight as Py.HCl, and heat it quite hard (normally 100°C or more).
Better if in a microwave reactor. And remember to use a pressure-resistant reactor!

If the butoxy you mention is a t-butoxy, though, I'm afraid you will have some trouble in differentiating the two ethers. You might check Greene's protective groups for selective deprotections.

It's a n-butoxy, I'm going to give it a try...  I checked Greene's book, but they do not really give selectivity between methoxy groups and other ethers.

Hi,

I did a lot of BBr3 demethylations during my PhD and did them in DCM at -78 0C and some did contain amide linkages! I think you might struggle to differentiate between a butoxy and methoxy group cleavage but doing at a low temp and monitoring by LC-MS might see if you have any chance. Would it be easier to change your approach? Without knowing your scheme one can't say but could u protect your methoxy phenol as a PNB group instead which is easily removed by DDQ and your butoxy won't be touched?

R.

Would you rise the temperature after initiating the reaction?  Normally, I let it warm up to RT, maybe better to keep the temperature low?
Indeed, this would be another approach, but quite difficult because the protecting group would have to survive 7 synthesis steps including a reduction, a Friedlaender and a deesterification.  But if in the end my demethylation seems hopeless, I'll give it a try 

[russellm72]

Yeah you can always try the reaction at lower temperatures.

Allow to warm in stages and analyse and if your a lucky bunny u might find u can take one off but leave the other! Most probably the butoxy group will come off first just to piss you off!!!

R