[techie]

I am trying to convert 2 secondary -OH groups in a molecule to methoxy groups. I have tried using dimethyl sulfate as the methylating agent under basic conditions. However, I am unable to get complete conversion of the the -OH groups to methoxy groups. I have a significant amount of monosubstituted product. I think the presence of water in the reaction may be the reason for this. Can someone suggest an alternate method for this?

Will using a mesylate/tosylate be a more effective approach than dimethyl sulfate? If yes, under what conditons would a tosylate react with the -OH group?

Thanks in advance.

[sjb]

Why do you want conversion to a bis methoxy containing compound? Conversion to a sulfonic ester (e.g. a mesylate or a tosylate) would activate the hydroxyl to displacement, whilst a methoxy group would not.

Depending on what else is in your molecule, how about hitting it with 2 equivalents of NaH or similar, then adding your two equivalents of Me⁺; I'm not sure whether one molar equivalent of Me₂SO₄ would do the trick here, or whether you'd still need two...

S

[techie]

Thanks for your reply. My final product is the molecule with the two methoxy groups. I do not intend to convert the methoxy groups to anything else.

What would be the function of the NaH? Provide a basic environment for the Me₂SO₄ to react?

[agrobert]

NaH will deprotonate the alcohol which could then attack something like CH3I methyl iodide to form your methoxy group.

[russellm72]

Hi,

Although your reaction may be basic at the beginning of the reaction have u added enough base to make sure it stays that way?

I'd agree with other poster use a couple of equivalents of NaH (60% in oil  probably) then add something like MeI or indeed quench with DMS.

Perhaps you need to pump the temperature up a bit to get the second one on. Have you considered this?

R.

[techie]

I do add additional base during the reaction with dimethyl sulfate to maintain basic conditions. In fact I alternately add small quantities of dimethyl sulfate and base. The typical reaction temperature is about 65-75 C. Like I said, I think the problem may be the presence of water that is generated. That could be eating up some (or maybe quite a bit) of the dimethyl sulfate sue to which I am unable to get complete conversion even after adding 1.5 molar equivalents of dimethyl sulfate.

Are there any issues with using NaH moistened with oil or does the oil tend to separate out?

[agrobert]

Use excess NaH ~2.5 equivalents.  Dissolve in dry hexane and swirl, decant the hexane which should readily remove mineral oil, repeat.  You should now have relatively dry NaH (white/gray solid), but use it quickly it will react with any moisture in the air.  I would recommend using methyl iodide instead of dimethyl sulfate.    Are there any other functional groups in your compound?

[techie]

Thanks so much. I will try this out.

[D|0XIN]

Hi there,

Have a read of this:
http://en.wikipedia.org/wiki/Williamson_ether_synthesis

The procedures section has some useful suggestions on catalysis (addition of a phase-transfer catalyst, soluble iodide salt, or silver salts).

[Custos]

You might also want to consider using diazomethane.