48 Letters in Organic Chemistry, 2011, 8, 48-52 1570-1786/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. Demethylation of Aromatic Methyl Ethers Using Ionic Liquids under Microwave Irradiation Mikko Passiniemi, Mikko J. Myllymäki, Juha Vuokko and Ari M.P. Koskinen* Department of Chemistry, Aalto University School of Science and Technology, P.O. Box 16100, FI-00076 Aalto, Finland Received April 28, 2010: Revised July 16, 2010: Accepted December 09, 2010 Abstract: An efficient demethylation reaction for aromatic methyl ethers has been developed. Deprotection reactions give high yields with butylpyridinium bromide under microwave irradiation. Basic and acidic functional groups are tolerated if the reaction is performed under acidic conditions. Keywords: Aromatic ether, demethylation, ionic liquid, microwave irradiation, solvent free. INTRODUCTION The nucleophilic (Lewis basic) or electrophilic (Lewis acidic) character of functional groups can be modified by modulating their specific character through the use of protective groups [1]. Ethers are useful protective groups for alcohols in synthetic chemistry. Methyl ether is considered to be the most effective protective group because of its high stability under a variety of reaction conditions. This stability towards reagents sometimes leads to harsh deprotection conditions, which in many cases give rise to side reactions and lower yields [2]. For the deprotection of alkyl aryl ethers a wide variety of reagents have been developed, including Lewis acids (e.g. BBr 3 [3], AlCl 3 [4]), Brønsted acids (e.g. Pyr• HCl [5]) and nucleophilic reagents (e.g. NaSEt in DMF [6]). These methods are often quite drastic and require high reaction temperatures, which often lead to decomposition of the substrate or unwanted side reactions. Consequently ether cleavage methods under milder conditions have been the focus of much attention. Ionic liquids (IL) have attracted scientists for years [7]. Their properties (low vapour pressure, recyclability, high thermal stability, ease of handling, functions as catalyst as well as reaction media) make them attractive for environmentally benign chemical processes. Ionic liquids have especially good response to microwave irradiation: they absorb energy very rapidly and at high temperatures they can function as reagents, thus making them attractive reactive solvents for chemical synthesis. IL have been used successfully in demethylation reactions of aromatic methyl ethers under microwave irradiation. Kulkarni et al. demethylated various aryl methyl ethers in pyridine hydrochloride under microwave irradiation [8]. They performed demethylations in 10 mmol scale in a closed round-bottomed flask with a five-fold excess of ionic liquid. Isolated yields varied between 74-95% for *Address correspondence to this author at the Department of Chemistry, Aalto University School of Science and Technology, P.O. Box 16100, FI- 00076 Aalto, Finland; Tel: +358 9 470 22526; Fax: +358 9 470 22538; E-mail: Ari.Koskinen@tkk.fi aromatic methyl ethers, being 78% for p-anisaldehyde. Chauhan and Jain broadened the scope by changing the ionic liquid to butylpyridinium bromide [bpy][Br] and 1-butyl-3- methyl imidazolium bromide [bmim][Br] [9]. Dealkylation was more facile in [bpy][Br] than in [bmim][Br] and reactions also gave slightly higher yields. Demethylations were conducted in 1 mmol scale both in the substrate and the IL. With [bpy][Br] the yields varied between 71% and 90%, being 86% for p-anisaldehyde. Dealkylation of aryl alkyl ethers using ionic liquids is reported to be efficient also without microwave irradiation. Driver and Johnson have shown 3-methylimidazolium bromohalogenates(I) [HmimBr-HBr] demethylate anisole and other ethers at room temperature [10]. Kemperman et al. have expanded the scope of this methodology to chloroaluminate ionic liquids ([TMAH][Al 2 Cl 7 ]) [11]. RESULTS AND DISCUSSION Encouraged by the results of Desai [8] and Chauhan [9] we examined the use of ionic liquids in the cleavage of an aromatic benzyl ether when hydrogenation was not a choice [12]. Debenzylation proceeded smoothly under microwave irradiation, albeit in our hands the reaction required more ionic liquid (200 mol-%) compared to previous results by Chauhan. We therefore decided to have a closer look at the demethylation reaction of aromatic ethers especially since detailed demethylation conditions have not been reported. To investigate and find the best conditions, we carried out demethylations in four different IL’s (Fig. 1); N-Bu 4 NBr, N,N-BuMeIm ([bmim][Br]), N,N-BuMe 2 ImBr ([bmmim][Br]) and N-BuPyBr ([bpy][Br]). p-Anisaldehyde was chosen as the model compound (Scheme 1). The substrate and the IL were mixed together and irradiated in a CEM Discovery microwave reactor in short cycles [13]. GC samples were taken after each irradiation cycle to determine the progress of the reaction. Conversions after five irradiation cycles varied between <20% (N-Bu 4 NBr) to 60- 70% ([bpy][Br] and [bmmim][Br]) based on GC analysis. With all four ionic liquids used, there was substantial formation of O-butylated phenol ether as a side product (by