Dear Eleni,

You may use a newly developed protocol features in-situ generation of sodium alkylthiolate using NaOH, and is almost free from foul smells and potentially harmful gases.

For the full procedure, please read the following publication:

Archives of Pharmacal Research

March 2008, Volume 31, Issue 3, pp 305–309

 Practical demethylation of aryl methyl ethers using an odorless thiol reagent

A highly practical method for demethylation of aryl methyl ethers employing a long-chain thiol has been developed. Under the conditions described herein, clean and fast conversions to the desired phenolic compounds have been achieved with a broad range of substrates. Unlike other thiolate-mediated methods, this newly developed protocol features in-situ generation of sodium alkylthiolate using NaOH, and is almost free from foul smells and potentially harmful gases. It therefore provides an attractive option for the demethylation of aryl methyl ethers.

http://link.springer.com/article/10.1007/s12272-001-1156-y

Hoping this will be helpful,

Rafik

One of the best procedures I tried long time ago for demthylation of methoxy aryls was using Ph2PLi; see the following reference for a guide and a procedure:

Demethylation of methyl aryl ethers: 4-ethoxy-3-hydroxybenzaldehyde

Organic Syntheses (1977), 56, 44-8

Another one to try is trimethylsilyl iodide

Dear Eleni!

May be an appropriate decision is a liquid adduct of thiourea and anhydrous aliminium chloride (1:2). No smell, no problem with solubility of starting material (neat reaction), easy workup. See patent US20080039643 for more information including useful overview on demethylation reagents with references.

Good luck!

If your compound is stable around 220°C, you may try the "good old" method: Pyridine hydrochloride. Have a look at this book: Greene's Protective Groups in Organic Synthesis (phenol protection/deprotection chapter).

Good luck !!!

Frédéric

You could try Boron tribromide (BBr3)in dichloromethane. I have performed deprotection using this reagent in equimolar basis. In my case I added BBr3 at 0oC and then raised the temperature gradually.

You can check the link for review article. There are many different methods available.

http://www.sciencedirect.com/science/article/pii/S0040402005008276

I like triethylsilane with tris(pentafluorophenyl)borane follwed by TBAF.  See V. Gevorgian Journal of Organic Chemistry (2000), 65(19), 6179-6186.  

You do not specify the type of aryl group e.g. phenyl, naphthyl  nor other substituents, etc nor give the type of heterocycle that is attached. The nature of the aryl group and substituents could be important. If the heterocycle is acid sensitive it may be falling apart in a mineral acid acid medium. If not pyridine hydrochloride, as recommended by F Balssa,  is actually very mild. Solubility should not be a problem as the reaction is run as a melt.  However as he suggested, consulting Greene and Wutz and their charts on functional group compatibility  may lead you to a workable solution.

Long ago I had a situation where demethylation of a 3-hydroxy-4-methoxyphenyl moiety did not work with a variety of reagents and conditions.  Catalytic hydrogenation of the benzyloxy analogue gave the desired compound.

Dear Eleni Kourtidou,

Good morning and I have read your question. I will suggest one reagent, I thing that  works for your case. The reagent is SODIUM THIO ETHOXIDE IN DMF SOLVENT AT REFLEX TEMPERATURE. Please try this method. sure it will work.

TMS iodide, as Thomas suggests, works extremely well on most ArOMe substrates.  No solvent needed, just slurry your material in excess reagent.  Workup consists of applying a vacuum.

All of the above are good suggestions. I'll just reiterate that your cannot use methanol as a co-solvent for Lewis Acid based reaction conditions. 

I am a fan of Boron Trifluoride Dimethylsulfide Complex in methylene chloride at zero degrees for 2 hours. Workup as usually with strong base.

Also another interesting condition is 5 equivalents of methionine in a solvent of methanesulfonic acid at 50 degrees. 

Another method is LiI (anhydrous) in refluxing pyridine.

Since TMSI is fairly prone to hydrolysis and is expensive, I recommend making it in situ by mixing NaI with TMSCl in MeCN with your substrate, then bring to reflux.

Good luck.

Since the process with BBr3 failed, you can try to demethylate methoxy group with Me3Si-I (TMS-iodide) . The reference is : Michael E. Jung, Mark A. Lyster; J. Org. Chem., 1977, 42 (23), pp 3761–3764. Also on many occasion, we got good result in demethylation of methoxy group present in an benzacridine system using NaSMe, DMF, reflux. You have to prepare NaSMe by reaction of Methyl mercaptan and Na, then to this solid NaSMe DMF solution of the compound is to be added. After reflux of 2-5 hours demethlaion is completed. It is poured in ice water, acidified wth AcOH and  extracted with DCM or filtered the phenolic substance. 

Dear Eleni,

Please, find in attach an article on: Demethylating Reaction of Methyl Ethers

By: ZHANG Jin-mei LI Yue-qing ZHAO Wei-jie*

They using varities of reagents, such as, BeCl2,Tolene; Nai-PrS,DMF; NaN(SiMe3)2

or LiN(i-Pr)2, THF,DMEU,1850C, sealed tube; FK-alumina, Ethylene glycol

5h;210-215 and SnO2,CH2Cl2.

Good luck

You can try with AlCl3 in toluene at reflux or at 160°C Under microwaves

You can try with pyridinium hydrochloride which is facile and can be done at any scale.

Check with this report.

Dear Eleni,

Please, find in attach a paper on demethylation of aryl methyl ether. It may be useful for you.

Good luck

Real thanks to you all for your time and your answers... I am going to take a look on your suggestions and also to try some of them. Too many suggestions to try..

Can use anhydrous pyridine hydrochloride.

Heat 30-40 equiv of anhydrous Py.HCl to 140 degree C kept under argon atmosphere (don't forget to attach condenser). Py.HCl will become liquid. To this add your methoxy substrate. Raise the temperature to 195-200 degree C with stirring. After 6 h cool it down to rt. add hot water. sonicate to make suspension. keep at 4 degree temp in fridge overnight. Filter. Suspend the solid in 4:1 EtOH:H2O. Neutralize by adding NaOH solution. Filter and wash with water.

Ethanethiol is also useful