Demethylation of aryl ethers.

CherrieBaby · chouchou

Cleavage of Alkyl o-Hydroxyphenyl Ethers
Robert G. Lange
J. Org. Chem. vol. 27, (1962), pp 2037-2039
Abstract: A facile cleavage of the vanillin methoxyl group has been discovered and the reaction has been successfully extended to a number of other alkyl o-hydroxyphenyl ethers.

http://rapidshare.de/files/1057727/ArOMe_Demethylation-Lange-JOC-27-2037-9_1962_.pdf.html (PDF, textified, 72 Kb)

CherrieBaby · chouchou

Selective Demethylation of Aryl Methyl Ethers.
B. Loubinoux, G. Coudert, G. Guillaumet
Synthesis 1980. pp 638-640
Summary: Hexamethylphosphoric triamide (HMPT) has been used for selective dealkylation of unsymmetrical actived aromatic ethers; usually giving good yields in reactions of polymethoxybenzaldehydes.

http://rapidshare.de/files/1057825/ArOMe_Demethylation_HMPT-Synthesis-1980-pp638-40.pdf.html
(PDF, searchable text, 113 Kb)

CherrieBaby · chouchou

Chemical Abstracts - 3 abstracts of aryl-ether demethylations.

Cleavage of phenol ethers with pyridine hydrochloride.
CA 4809(7), (1942).
Abstract of: Vinzenz Prey. Ber. 74B, 1219-25 (1941).

Dealkylating alkoxy aromatic amines.
CA 44, 5909b (1950).
Abstract of: Curt G. Vogt and Franz Marschall. USP 2497248

Selective cleavage of ethers by aluminum chloride.
CA 52, 6255h, (1958).
Abstract of: Cs. Szántay. Acta Chim. Acad. Sci. Hung. 12, 83-91 (1957).

http://rapidshare.de/files/1058043/CA-dealkylations.html.html
(HTML, text 10 Kb)

CherrieBaby · chouchou

Dealkylation of Activated Alkyl Aryl Ethers Using Lithium Chloride in Dimethylformamide
Angela M. Bernard, M. Rossella Ghiani, Pier Paolo Piras, Antonio Rivoldini
Synthesis, 1989, pp. 287-289

Alkyl aryl ethers having electron-withdrawing substituents in the ortho or para positions are easily cleaved with lithium chloride in dimethylformamide.

http://rapidshare.de/files/1145254/LiCl-DMF.demethylation_Synthesis.1989.pp287-9.mht.html
(28 Kb, HTML, MS Web archive)

CherrieBaby · chouchou

A Stabilized Formulation of IBX (SIBX) for Safe Oxidation Reactions Including a New Oxidative Demethylation of Phenolic Methyl Aryl Ethers
Aurélie Ozanne, Laurent Pouységu, Dominique Depernet, Bruno François, and Stéphane Quideau
Organic Letters 2003, Vol. 5, No. 16, pp. 2903-2906

Abstract: SIBX is a nonexplosive formulation of IBX that can be used as a suspension in a variety of standard organic solvents such as refluxing EtOAc and THF to oxidize safely alcohols into aldehydes and ketones. The use of hot THF is limited to the oxidation of allylic and benzylic alcohols. Most yields are comparable to those obtained with IBX or DMP. SIBX can also be used to perform oxygenative demethylation of 2-methoxyarenols into orthoquinones and catechols.

http://www.simafex.com/_pdf/organic_letters.pdf

http://rapidshare.de/files/1145318/SIBX.Aryl-Methyl.demythylation_Org.Lett.2003.v5.p2903.pdf.html

(PDF, 90 Kb, non-encrypted text)

CherrieBaby · chouchou

Demethylation of Methyl Aryl Ethers using Pyridine Hydrochloride in Solvent-free Conditions under Microwave Irradiation
P. P. Kulkarni, A. J. Kadam, R. B. Mane, Uday V. Desai, P. P. Wadgaonkar
J. Chem. Research (S), 1999, 394-395

Abstract: Methyl aryl ethers are deprotected in high yields using pyridine hydrochloride in the absence of solvent under microwave irradiation

http://rapidshare.de/files/1145440/Pyridine_demythylation_J.Chem.Res._S_.1999.pp394-5.pdf.html
(PDF, 87 Kb, non-encrypted text)

Lego · Thu Sep 29, 2005 9:07 pm

For details and reaction schemes:
http://lego.chemistry.tripod.com/various/demethylation.html

Cleavage of aromatic methyl ethers with ethanethiol (EtSH) and aluminium chloride (AlCl3)
Hard Acid and Soft Nucleophile System.
2. Demethylation of Methyl Ethers (of Alcohol and Phenol with an Aluminum Halide-Thiol System
Manabu Node, Kiyoharu Nishide, Kaoru Fuji, and Eiichi Fujita
J. Org. Chem., 1980, 45(22), 4275-4277

Selective Deethylation of 4-ethoxyybenzoic acid ethylester

To a mixture of dry ethanethiol (1 mL) and dichloromethane (1 mL) was added aluminum chloride (0.40 g, 3.0 mmol) at 0 °C. The resulting solution was warmed to room temperature, and 4-methoxybenzoic acid methylester (0.194 g, 1.0 mmol) was added with stirring. After being stirred for 9.5 h, the reaction mixture was poured into water, acidified with dilute HC1, and extracted with dichloromethane. The organic layer was treated as usual to give a crude product. Chromatography over a silica gel column gave 4-hydroxybenzoic acid ethyl ester (0.157 g, 95.5%) identical with an authentic sample.

Demethylenation of 1,3-benzodioxole

To a solution of aluminum bromide (0.683 g, 2.4 mmol) in dry ethanethiol(2 mL) was added 1,3-benzodioxole (0.122 g, 1.0 mmol) at 0 °C. After being stirred for 0.5 h, the reaction mixture was poured into water, acidified with 3% HC1, and then extracted with ether. The ethereal layer was shaken with 1% aqueous KOH. The aqueous layer was acidified with 3% HC1 and again extracted with ether. The ethereal layer upon the usual workup gave a crude product, which was chromatographed over a silica gel column to afford pyrocatechol (86.5 mg, 78.4%).

Selective Demethylenation of of 3,4-methylendioxy benzoic acid methyl ester

To a solution of aluminum bromide (0.537 g, 2.0 mmol) in dry ethanethiol(2.3 mL) was added 3,4-methylendioxy benzoic acid methyl ester (0.091 g, 0.5 mmol) at 0 °C. After being stirred for 1 h at 0 °C, the reaction mixture was poured into water, acidified with 5% HCl, and then extracted with ether. The ethereal layer was treated as usual to give a crude product, and chromatography over a silica gel column gave protocatechuic acid methyl ester (61.3 mg, 72.4%), identical with an authentic sample prepared from protocatechuic acid.

Cleavage of aromatic methyl ethers with 1-dodecanethiol (C12H25-SH) and aluminium chloride (AlCl3)
Odorless substitutes for foul-smelling thiols: syntheses and applications
Manabu Node, Kamal Kumar, Kiyoharu Nishide, Shin-ichi Ohsugi and Tetsuo Miyamoto
Tet. Lett., 2001, 42(52), 9207-9210

4-methoxybenzoic acid methyl ester is cleaved to 4-hydroxybenzoic acid methyl ester at r.t. in 4,5 h (yield: 77%).
Cleavage of aromatic methyl ethers with 1-dodecanethiol (C12H25-SH) and sodium methoxide (NaOMe)
Practical synthesis of a highly functionalized thiazole ketone
Lisa F. Frey, Karen M. Marcantonio, Cheng-yi Chen, Debra J. Wallace, Jerry A. Murry, Lushi Tan, Weirong Chen, Ulf H. Dolling and Edward J. J. Grabowski
Tetrahedron, 2003, 59(33), 6363-6373

Many standard demethylation conditions were screened for the transformation of 6 to 8 (Scheme 4). In several cases (i.e. boron tribromide), competing cleavage of the cyclopropyl ether was a problem. Fortunately, the use of a slight excess of sodium ethanethiolate in N,N-dimethylformamide (1-Methyl-2-pyrrolidinone and dimethylacetamide were also acceptable solvents for this reaction) at 100°C effected clean demethylation of 6 with no detected cleavage of the cyclopropyl ether.

Scheme 4: EtSNa or CH3(CH2)11SH and NaOMe, DMF, 100°C, 1 h

Because the stench of sodium ethanethiolate and the reaction byproduct, ethyl methyl sulfide, made this reaction unpleasant to run on a large scale, we were interested in carrying out the same transformation under non-odorous conditions. Recent papers discuss the use of long chain thiols to minimize odor so we used this work as a basis for choosing a long chain thiol for our demethylation reaction. Following a literature result, the use of mixtures of a thiol and various lewis acids was explored.19 Unfortunately, these reactions were not successful on our substrate; however, employing the sodium salt of a thiol afforded clean demethylation. Hence, the use of 1.7 equiv. of dodecanethiol and 1.7 equiv. of sodium methoxide in N,N-dimethylformamide at 100°C gave an almost quantitative yield of phenol 8. Work up involved extraction of the product into aqueous base with thiol byproducts left behind in the organic phase. The product was extracted from the aqueous layer simply by adjusting to acidic pH. This work up provided an odor free solution of compound 8 that was used in the next reaction without further purification. Due to our success with demethylation using a non-odorous long chain thiol, we explored the generality of the method with a few model compounds. Using the procedure described above for the conversion of 6 to 8, the compounds shown in Table 1 were readily demethylated by heating each substrate with sodium methoxide and dodecanethiol in N,N-dimethylformamide at 100°C. Demethylation of 4-methoxybenzonitrile and methyl 2-methoxybenzoate (Table 1, entries 1 and 2) proceeded in high yield. Demethylation of hindered 2,6-dimethylanisole (Table 1, entry 3) was sluggish and did not go to completion. Interestingly, selective (4.9:1) demethylation of 3,4-dimethyoxybenzonitrile (Table 1, entry 4) was observed, with preference for demethylation para to the electron withdrawing nitrile substituent. Clearly, these results demonstrated that demethylation using a non-odorous long chain thiol and sodium methoxide was a viable alternative to sodium ethanethiolate for a range of anisole related substrates.

Table 1: Demethylation using sodium methoxide and 1-dodecanethiol in N,N-dimethylformamide at 100°C

Entry Starting material Product(s) Yield
1
4-methoxybenzonitrile
4-hydroxybenzonitrile 97%
2
4-Methoxy benzoic acid methyl ester
4-Methoxy benzoic acid 89%
3
3,4-Dimethoxy benzonitrile
3-Hydroxy-4-methoxy benzonitrile 17%

4-Hydroxy-3-methoxy benzonitrile 83%
4
2,6-Dimethylanisole
>2,6-Dimethylphenol 75%a
a 21% starting material recovered

3-(Cyclopropyloxy)-4-hydroxybenzonitrile 8
To a solution of 6 (47.7 g, 0.252 mol) in DMF (450 mL) was added 1-dodecanethiol (104 mL, 0.432 mol) followed by NaOMe (23.4 g, 0.432 mol). The mixture was heated to 100°C and aged for 1 h (monitoring by HPLC). After cooling to RT, iPAc (404 mL), water (518 mL), and 5N NaOH (45 mL) were added and the layers mixed well. The aqueous layer was washed with iPAc (350 mL) to remove more thiol byproducts. The aqueous layer was neutralized to pH 6 by addition of conc HCl (45 mL), and the product was extracted into iPAc (518 mL). The aqueous layer was extracted with iPAc (278 mL then 150 mL). The organic layers were concentrated and flushed with 160 mL DMF (43.7 g, 99% yield of 8 as compared to a chromatographed standard) before being used directly in the difluoromethylation.

CherrieBaby · chouchou

The files here mentioned above have become out-of-date. I have re-named and zipped 6 of them together. Here is the new link.

http://rapidshare.de/files/5841538/ArOMe_Dealkylations.zip.html

9,910 ArOMe_Dealkylations_Chem.Abstracts.html
73,367 ArOMe_Demethylation-Lange-JOC-27-2037-9(1962).pdf
115,685 ArOMe_Demethylation_HMPT-Synthesis-1980-pp638-40.pdf
27,966 ArOMe_demethylation_LiCl-DMF_Synthesis.1989.pp287-9.mht
89,088 ArOMe_demythylation_Pyridine.HCl_J.Chem.Res.(S).1999.pp394-5.pdf
92,040 ArOMe_Demythylation_SIBX_Org.Lett.2003,v5,p2903.pdf

The numbers above on the left column are file sizes (in bytes).