Melgar
Anti-Spam Agent
Posts: 2004
Registered: 23-2-2010
Location: Connecticut
Member Is Offline
Mood: Estrified
|
|
Aryl methoxy groups selectively cleaved to phenols by lithium iodide
The original paper uses 2,4,6-collidine, something that I'd prefer not to try and source, but later references seem to imply that dimethylformamide
can also be used.
Everything has to be very anhydrous from the looks of it, although lithium iodide can be prepared anhydrous using iodine and lithium metal. The two
elements don't react with each other nearly as vigorously as other alkali metal/halogen pairs do, since they're both the least reactive in their group
and the size difference seems as though it'd limit the reaction kinetics. However, it's important to use an excess of iodine, which could presumably
be dissolved and removed by a suitably nonpolar solvent. It's easy to accidentally overestimate how much of your lithium metal has oxidized, use a
bit too much, and have a crimson lithium fire to deal with later on. (Fortunately, it was small and did no damage. Important to only ever perform
reactions that are expected to be vigorous on a very small scale!)
Still, if this works, it'd certainly be a lot more accessible than boron tribromide or whatever unobtanium-catalyzed reaction has recently become
popular.
Attachment: lithium_iodide_methoxy_cleavage.pdf (83kB)
This file has been downloaded 397 times
The first step in the process of learning something is admitting that you don't know it already.
I'm givin' the spam shields max power at full warp, but they just dinna have the power! We're gonna have to evacuate to new forum software!
|
|
|
AvBaeyer
National Hazard
Posts: 644
Registered: 25-2-2014
Location: CA
Member Is Offline
Mood: No Mood
|
|
Melgar,
You are correct in that strictly anhydrous conditions are required for optimal results. I wonder if sodium iodide in combination with lithium bromide
(both are easy to find) in hot DMF might work. Both salts have good solubility in DMF but I believe that sodium bromide is relatively insoluble so you
would generate lithium iodide in situ.
Just as an aside, anhydrous ferric chloride in acetic anhydride will cleave aliphatic ethers. Alkyl aryl ethers are also cleaved but a complicating
side reaction is acylation of the aromatic ring in Friedel-Crafts fashion (this I know from hard experience). See
Ganem, B.; Small, V. R., Jr. J Org Chem 1974, 39, 3728.
Alexakis, A.; Gardette, M.; Colin, S. Tet Letters 1988, 29, 2951.
AvB
|
|
|
Dr.Bob
International Hazard
Posts: 2658
Registered: 26-1-2011
Location: USA - NC
Member Is Offline
Mood: No Mood
|
|
Pyridine is often used as the solvent in these reactions, the pick of solvents often is determined by how how hot you need to heat a particular
reaction. If you don't see a reaction in pyridine after a certain time, then you would need to use a higher BP solvent. These reactions are often
slow and stinky, but if the rest of the molecule is stable to the conditions, they work pretty well. There needs to be a certain (can be pretty small
flow) amount of inert gas flow through the reaction to sweep away the methyl iodide formed, or they fail to go to completion.
And using a mix of lithium salts is likely fine, most of the salt will stay insoluble until some methoxy reacts even with lithium iodide to form
methyl iodide and lithium salt of the phenol.
|
|
|
tsathoggua1
Hazard to Others
Posts: 335
Registered: 8-1-2017
Location: Beyond the pale
Member Is Offline
Mood: Phosphorescent
|
|
Just a point, at least with aryl alkyl ethers, there would be a potential for the use of pyridine to contaminate the results of testing such systems,
since it is capable of demethylating at least some aryl methyl ethers. In fact it has a historic use in new zealand in what the new zealanders call
'homebake', this is more or less heating extracted codeine from OTC tablets in a sealed tube with pyridine, which (selectively?) demethylates the 6'
methyl ether to the phenol (morphine) and then possibly going on to acylation.
So this is already a known reaction with pyridine alone, Dr Bob. Yields are typically in the region of 30% in the case of 'homebake' according to what
I have read of the process, its meant to be touchy and require an experienced hand at it before anything like 30-40% is reached. 40% would take
somebody who has really mastered that particular application.
Another process (which doesn't involve creating the toxic MeI as a side product which if not removed is likely to remethylate the phenol, prolonging
reaction time) that might be considered is demethylation using a combination of sodium dodecanethiolate and sodium or potassium tert-butoxide, in DMF.
There are a few papers around on it, dodecanethiol seems to be the best of the bunch to use, have heard from somebody who tried it (on dihydrocodeine)
using Na propanethiolate that they got an intractable mess). Dodecanethiol is according to some papers, relatively stench-free. However when I ordered
some to test this (which hopefully I'll be in a position to do soon) the bottles arrived WELL sealed and with large 'stench' warning on them. This
could be a generic 'oh this is a mercaptan, its going to fucking reek' moment on the part of the seller but I couldn't tell you personally. Some
papers I've read in the past tested a few different ones and it seems dodecyl is the right chain length more or less exactly both not to be too
volatile but more importantly, doesn't seem according to past reading at least, as if it binds with nasal olfactory receptors that well, and
accordingly was voted the least vile out of several mercaptans tested. Have read of much MUCH better yields than the pyridine method. Indeed, one
paper reported upwards of 90%. And even some paper I'm still trying to find again reported good yields using codeine as a substrate.
Have heard tell of attempts being made at -10 'C in CH2Cl2 with the same reagent system, Na-propanethiolate and KOtBu or NaOtBu. But that was only in
passing, not sure what came of that.
Edit-in the majority of these reductions, DMF was used as solvent.
[Edited on 25-6-2017 by tsathoggua1]
|
|
|
tsathoggua1
Hazard to Others
Posts: 335
Registered: 8-1-2017
Location: Beyond the pale
Member Is Offline
Mood: Phosphorescent
|
|
Ahem, didn't realize, forgot to add, that it was the attempt in dichlor that was read as a snippet, not much more detail than time and temperature.
The attempt with Na-propanethiolate didn't work (personal communication) can supply details of the failed experimental if wanted.
|
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
