[bsd]

Hi Guys,

This is mainly a question for anyone with a bit of experience in this area.  I have prepared a simple p-methoxyphenone from anisole and the corresponding acid chloride via FC acylation and now wish to cleave the methyl ether.  I have tried what appears to be the (albeit nasty) go-to reagent -- boron tribromide -- with limited success.  After stirring at rt for 24 h I still have a substantial amount of starting material remaining and multiple products forming (I should confess I'm asking for general advice before I know the precise problem with the tribromide demethylation since I haven't finished working it up).  I guess my main questions are:

(1) If yields are low with boron tribromide is it worth screening other conditions?  The Lewis acidity of most other reagents doesn't seem to rank anywhere near BBr3.

(2) Does BBr3 tolerate alkyl chlorides elsewhere in the molecule?  As I understand the demethylation mechanism, free bromide performs SN2 at the methyl carbon, displacing the (activated) boronate-phenol complex.  I was working on assumption that bromide isn't going to displace my alkyl chloride at rt, but if I go to refluxing 48% HBr/AcOH I suspect this is going to be a serious problem... Is there much risk if I use a healthier excess of BBr3 (used 2.5 eq, 1 eq for the ether, 1 eq for the ketone and .5 eq because the bottle is old)?  Does anyone ever heat these things?

(3) Can phenolates have substantial solubility in organic solvents?  The workup I went with was basically quenching the RM with ice/HCl, separating the organics, extracting aqueous with ether a few times, combining organics then (in attempt to avoid a column) extracting into 1M NaOH several times (yellow colour moving into the aqueous), acidifying and extracting back into ethyl acetate.  After drying and concentrating the ethyl acetate I ended up with very little mass and it basically looked like brown oily junk.  Most of the mass and the (strongest) new spot(s) on TLC that I suspected was my product (about half the Rf of the SM, consistent with a phenol) ended up staying mostly in the ether phase (ie. did not move into the 1M NaOH).  Should I take this as good evidence that those spots are not phenols?  Does anyone have any gut feelings for possible side products of this reaction? (My molecule is simply a p-methoxyphenone with a beta chlorine primed for elimination in presence of base).

(4) Any other advice on performing this transformation?  The reason I have used the methyl ether is that I found it very difficult to get a clean Fries rearrangement of the phenol ester to go and I wanted to avoid the extra step of adding my PG by using anisole as my starting material.  If this doesn't work I'm going to have to look at putting a MOM ether (stable to FC acylation?) or something on phenol myself; or perhaps on p-bromophenol and generating the Grignard.

Thanks in advance.

[enahs]

I have had quite a good bit of success with BBr3 for doing this. It took me a lot of tries to get it right though.

First, what solvent are you using? It has to be VERY dry and you have to perform the reaction under inert environment. Ultimately what worked best for me was dichloromethane as s solvent. Even though it is not miscible with water, regular dichloromethane is not even close to dry enough.Water is going to kill your reaction. I would quench my reactions by dumping into water.
The other advantage of using dichloromethane as the solvent is, boron tribromide is cheaper, easier, and safer to work with if you buy it already in a solution of dichloromethane.

Now, my substrate was NOT soluble in dichloromethane, but that did not matter. Just give it enough time and it goes.


I unfortunately do not have the paper with me, but many years back there was a very detailed study on BBr3, and at minimum it seems you want at least a 4:1 ratio of excess BBr3. It has been ~3 years since I did anything with it, so I do not remember why. You might want to see if you can find that paper. It is OLD, I had to copy it from a library and never scanned it. If I remember correctly, if there are other OH groups, you need to add an equivalent for that as well even though it does not modify it in the end? But, I am really not sure on the details? I would say for 100% sure you are not using nowhere near enough.

And they also found that it decomposes or is inactivated at R.T. more readily, or something. So cold is the way to go. I have never seen anybody do it at R.T.


My reactions were performed in a dry ice/acetone bath, under inert atmosphere, over night, with ultimately ~6 equivalent BBr3, with CH2Cl2 as solvent. The next day I would slowly warm to room temperature, and slowly poor reaction into water. Then do my workup.


I also experimented with HBr with not much luck, to many other side products. I did some experimenting with HI (similar to HBr), and for my substrates I had much better success, but nowhere near as good as success as once I got the BBr3 method working; just because BBr3 was so much more specific and I got much purer products.

[bsd]

Sorry I should've given my conditions: DCM freshly distilled from CaH2, BBr3 added neat (albeit from old bottle; looks fine though, only pale yellow; we have a bottle of 1M in DCM but it looks rank) at -77C under Ar, substrate added and RM allowed to warm to rt and stir for 24 h.

I might know the paper you're referring to: Tetrahedron (1968) 24 pp 2289-.  The reason several equivalents are generally required is that (as a super Lewis acid), BBr3 rapidly complexes anything that looks vaguely like it might be able to donate electrons (ketones, esters, nitriles, you name it...).  In my substrate the only heteroatoms are the ether I wish to cleave, an aryl ketone (for which I add an extra equivalent) and a chlorine (which shouldn't matter).  This paper claims 92% cleavage for p-methoxybenzoic acid which is the most comparably deactivated ring they screened (and they used 2.3 eq, beginning -80, warming to rt o/n).

I assume you didn't maintain your dewar at -77C overnight?

I suppose there isn't much harm in upping the equivalents to 5 or so (though I have trouble seeing how it will help unless the clean appearance of my BBr3 is misleading me and it has substantially decomposed).

I may in the end be better off taking your word that the reaction is finicky and abandoning it in favour of a different route!  I may have already invested more time than I should have in making what is essentially starting material.

[enahs]

Yes, I did keep it cold over night in the dry ice/acetone bath.

[OC pro]

6 equivalents is way too much. In your case with the acetophenone I would add an extra equivalent of course but normally 2equiv. BBr3 will do the job (if the quality is o.k.) BBr3 neat is in fact colourless (I distilled it once...it was nasty), but the reagent you get from Aldrich or Acros is somehow orange and can be kept at RT and stored for several weeks (although it fumes nasty).
The normal procedure would be as follows. Adding the reagent at -78°C to a solution of starting material in dry DCM slowly with following the internal temperature! After the reagent has been added, stir for 30min at -78°C and make a TLC!! Quench a small aliquote (taken out by a 1ml syringe ~0,1ml) of the reaction with methanol, then water. If no conversion occurs, you can warm in your case to 0°C. Stir for 1h at 0°C and make another TLC. You should see a bit of conversion. If it is still too slow you can warm to RT and stir until complete conversion. If the reaction will not proceed you can add another equivalent BBr3 (at 0°C).
By the way refluxing in 48% HBr should also do the job with your fairly tolerable substrate. 

I can only advise again and again: do proper reaction monitoring with TLC (or GC-MS). This is what the young students have to get in their brains. Don´t simply follow literature protocols like: "uhm they have warmed to RT and stirred for 24h and so do I" and at the end everything is decomposed. There is so much scientific fraud outside in the literature (especially from the 1980`s up to today). 

[bsd]

This bottle of BBr3 is years and years old.  That being said I'm confident it's still OK.  BBr3 is stable as long as it is stored correctly and this bottle still fumed like crazy (even after I vented the massive amount of pressure that had built up over the years -- pretty scary).

The TLC does not change qualitatively (number of products), but only in the strength of the SM spot between 30 mins of stirring (still at -77C) and 24 h (warmed to rt).

Refluxing 48% HBr will tolerate an aliphatic chloride?

[bsd]

I should also ask, seeing as though you've used it neat, how did you get it out?!  When my needle hit the liquid it started bubbling (BBr3 attacking the needle I presume), and when I tried to draw up the liquid most of what I got was gas.  I only managed to fill about 15% of the syringe, even by drawing the plunger the whole way.  Luckily that was all I needed for my trial scale reaction...  Do you cool the bottle to -40C or something?

[OC pro]

Yeah, I just took it out by syringe. As you mention it is years old you can simply throw this stuff away. Buy a new bottle. It´s just waste of time if you don´t know if your reaction gets spoiled from old/decomposed reagent. And multiple spot formation on TLC sounds like something wrong is going on. An alkyl chloride should be just fine if it is primary.

[bunky]

I've done this reaction on an acetophenone with four methyl ethers (hacking them all off - 40 equivs of BBr3!!!! ).  The previously mentioned procedures work just fine.  For myself, I just keep it at dry ice acetone temperature for most of the day and let it run over night.  Since I was working at large scale, for the quench i cooled it down to zero and had the flask vented via tube over a beaker of sat. NaOH and added water dropwise, then proceeded with the extraction after the quench. 97% yield.

[fledarmus]

I've done a lot of demethylations with BBr₃ and old bottles, no matter how good they look, just never seem to work. I have the luxury now of getting a new bottle of BBr₃ in dcm solution, using it until the seal starts to degrade, and tossing it. That saves me a lot of frustration.

[opsomath]

A chemist whom I respect suggests using very low temperatures, then step by step increasing; -89, -40, -10 to 0, then 20. TLC at each step after reasonable periods to see if your reaction is working.

Same guy also recommends molten pyridinium chloride as a good reagent for this, but I never tried it myself. My only experience personally with this one was p-methoxyiodobenzene, and that worked fine starting at dry ice-acetone and warming to RT to quench. DEFINITELY dry your solvent over CaH2 first.

[zolarpwr]

I saw a paper where they demethylated vanillin with AlCl3 and pyridine. Try and do a search for that.

If you ranked Lewis acids, Al is way stronger than B.