mnick12
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Protecting phenols in a grignard reaction
So some time in the near future I would like to prepare a Grignard from m-bromophenol, but that OH is going to mess things up. My question is what are
some protecting groups that are stable to Grignards, and relatively easy to remove? After some reading I have run across a few including
benzylsulfonyl and silyl ethers. Now both of those options sound nice but silyl ethers are out of reach for me. Benzylsulfonyl seems to be nice since
it could be prepared rather easily from benzyl alcohol, thiourea, and TCCA. The problem one would run into is removing the benzylsulfonyl from the
finished product. The abstract I am referring to uses Hydrogenolysis with raney nickel, but I cannot get raney nickel.
Any ideas?
Benzylsulfonyl
ethers
BTW if anyone has the full article for that first link I would highly appreciate a link to it.
Thanks!
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vulture
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I don't know what the intended use of your Grignard is, but you could methylate the phenol, then remove it after reaction with BBr3. This is quite
aggressive, though.
One shouldn't accept or resort to the mutilation of science to appease the mentally impaired.
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Chordate
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Benzyl chloride is a classic protecting agent for this sort of thing, and can be removed gently with Pd/C, but if you can't get raney then you might
not be able to get other catalytic agents.
Whats your budget and access like? A lot of these things can just be ordered. Alternatively, what are you trying to stick on that ring?
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madscientist
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Benzyl ethers can be cleaved in other ways too - strong acids, oxidation to benzoate and removal with base, Lewis acids such as
FeCl<sub>3</sub> etc...
I weep at the sight of flaming acetic anhydride.
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mnick12
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Sounds like benzyl ether is the way to go!
@Chordate: I can get 5% Pd on C, 10% Pd on Alumunia, 5%Pd on CaCO3 poisoned with lead, and 5% Pd on BaSO4. Do you happen to know the conditions
required for the cleavage of benzyl ethers? Would stirring with an over pressure of H2 and a catalyst achieve the desired results, or is this a high
pressure thing?
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Mark Van Adium
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I assume if you can't make a sillyl ether you're also unable to use dihydropyran? Easy to deprotect with HCl.
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Chordate
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5%Pd/C or 10%Pd on alumina should work. Poisoned catalysts are usually used for partial reduction.
Its an 'elevated pressure' reaction. In a lab they'd likely use a gas manifold at like 3 atm, but for just removing the protecting group a balloon
filled with hydrogen taped over the apparatus with stirring and gentle heat should pop that protecting group off in 3-4 hours (Don't quote me on that
3-4 hours mark, it may be longer. You might benefit from monitoring the progress with some simple chromatography).
Also, as mad scientist said, they can be cleaved other ways. HBr can work. all kinds of things can work.
And Pd/C is wonderful stuff, just remember that its temperamental even after you've finished the reaction, and you should work-up carefully and poison
it when you're done with it.
[Edited on 24-2-2011 by Chordate]
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UnintentionalChaos
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Aside from benzyl ethers, how about methoxymethyl, ethoxyethyl, or related ethers? They are fairly trivial to remove after reaction with acid since
the protected group is turned into an acetal. I'm not sure how easy they are to apply to phenols though...
Department of Redundancy Department - Now with paperwork!
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Nicodem
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Quote: Originally posted by mnick12  | | So some time in the near future I would like to prepare a Grignard from m-bromophenol, but that OH is going to mess things up. |
There is plenty of literature on preparing and using O-protected 3-bromophenol grignard reagents as these are commonly used to synthesize various
industrially important opioids. I suggest you to review the literature and patents. If I remember correctly, the easiest way is to simply start with
3-bromoanisole instead and do the demethylation at some later stage in the synthesis. If any of the later intermediates can tolerate strong
nucleophiles like thiolates or alternatively acids like HBr or BBr3, then consider this as an alternative approach. If however any later intermediates
tolerate hydrogenation, just benzylate your phenol and start with the benzyl ether (magnesium metal can cleave the benzyl aryl ether bond, so the
grignard forming conditions need to be mild).
The protection with ethyl vinyl ether to give the ethoxyethyl protecting group mentioned in the previous post is also a simple alternative using
simple reagents (cat. iodine, ~0.5 mol% or less, can be used to introduce the protecting group). The methoxymethyl group requires the use of
methoxymethyl chloride or bromide which are not something anyone wants to have anything to deal with.
http://www.organic-chemistry.org/protectivegroups/hydroxyl.s... (<- this is for the hydroxy group in general, so double check before applying
to phenolic hydroxy!)
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unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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