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Regular Article ORGANIC CHEMISTRY RESEARCH Published by the Iranian Chemical Society www.orgchemres.org Org. Chem. Res., Vol. 3, No. 1, 73-85, March 2017. A Tandem Scalable Microwave-Assisted Williamson Alkyl Aryl Ether Synthesis under Mild Conditions M. Javaheriana,*, F. Kazemib, S.E. Ayatib, J. Davarpanahb and M. Ramdarb aDepartment of Chemistry, Faculty of Sciences, Shahid Chamran University of Ahvaz, Iran. Ahvaz, Golestan Blvd, P. O. Box: 6135743135 bDepartment of Chemistry, University for Advanced Studies in Basic Sciences, Zanjan, Iran. Gava Zang, Zanjan, 45195-1159, Iran (Received 10 July 2016, Accepted 7 June 2017) An efficient tandem synthesis of alkyl aryl ethers, including valuable building blocks of dialdehyde and dinitro groups under microwave irradiation and solvent free conditions on potassium carbonate as a mild solid base has been developed. A series of alkyl aryl ethers were obtained from alcohols in excellent yields by following the Williamson ether synthesis protocol under practical mild conditions. Scale up ability of this practical procedure is shown by the preparation of some of the valuable dialdehydes up to 50 mmole from alcohols. The method is simple, rapid, straight-forward and holds potential for further application in organic synthesis and industrial requirements. Keywords: Tandem, scalable, Williamson ether synthesis, Alkyl tosylate, Microwave irradiation, Bis-2-nitrophenoxy akyl ether, Bis-2- formylphenoxy alkyl ether INTRODUCTION solvents [17,18], narrow substrate scopes [19], or noncommercial sophisticated catalysts [20], with long Alkyl aryl ethers are important solvents and synthetic reaction times [21], and also harsh reaction conditions, building blocks for the production of fragrances, cosmetics, which limits the attractiveness of some of these methods, pharmaceuticals and dyestuffs with emphasis on derivatives especially for large-scale or industrial applications. of phenols, naphthols and dihydroxybenzenes [1]. The most Since 1990s, a global movement to environmental three important methods in ether formation includes: (1) the protection and more economically beneficial approach in Williamson ether synthesis [2], (2) the Mitsunobu reaction scientific and industrial researches has been emerged, which [3], and (3) the Ullmann condensation [4-9]. Among them, is known as green chemistry [22]. Therefore, alternative the Williamson´s procedure seems to be the most straight- methods that are more compatible with the green chemistry forward way, that provides the best generality for the protocol are still needed. Herein, we wish to introduce a preparation of both symmetric and unsymmetrical ethers more practical and greener version of the noncatalytic [1,10]. Although, the Williamson ether synthesis in solution Williamson ether synthesis by using microwave irradiation has been well-known for almost 160 years, there are a few and solvent-free conditions to prepare alkyl aryl ethers from useful procedures available for direct conversion of phenols alcohols. into aromatic ethers, without requirement of pre-formation of the corresponding phenoxide ions or other reactive EXPERIMENTAL groups [11,12]. Nevertheless, these reactions are usually performed by General using organic solvents [13], phase-transfer catalysts [14,15], All reagents were purchased from Aldrich or SD Fine high temperature [1], strong bases [16,17], undesirable Chemicals and were used without further purification. Products were separated and purified by different *Corresponding author. E-mail: [email protected] chromatographic techniques and were identified by the Javaherian et al./Org. Chem. Res., Vol. 3, No. 1, 73-85, March 2017. comparison of their Melting point and NMR with those mmol, 0.56 g) was added again, and ground, thoroughly, reported for the authentic samples. FT-IR Spectra (neat) until complete elimination of TsCl, according to TLC were recorded on BOMEM Inc. 450 instrument. NMR monitoring. Then, phenol (15 mmol, 1.41 g) and DMF (1 Spectra were recorded on Bruker Avance DPX (400 MHz) ml) were added to the above mixture and mixed thoroughly. in CDCl3 and D2O with TMS as internal standard for The reaction mixture was transferred to a pyrex beaker (200 protons and solvent signals as internal standard for carbon ml) and placed inside the microwave oven and irradiated for spectra. Chemical shift values are reported in δ (ppm) and 40 s. Upon completion the reaction, monitored by TLC (n- coupling constants are given in Hz. The progress of all hexane/EtOAc, 4:1, V/V), the reaction vessel was cooled to reactions was monitored by TLC on 2 × 5 cm pre-coated room temperature. The desired product was extracted by n- silica gel-60 F-254 plates of thickness of 0.25 mm (Merck). hexane (3 × 50 ml) and washed with H2O (2 × 50 ml). The The chromatograms were visualized under UV 254-336 nm solvent was dried by anhydrous CaCl2 and evaporated by or by immersion in tanks of common chemical visualizer vacuo-rotary. 1-Phenoxyoctane was obtained in 93% yield such as DNP, H2SO4(conc.), I2, etc. (Table 2, entry 1). Attention: It should be noted that, for the reaction of Method A: Preparation of Alkyl Aryl Ethers by the oligoethylne glycols and benzylic alcohols with TsCl, after Reaction of Phenols with Alkyl Tosylates on K2CO3 completion the reaction, according to TLC monitoring, Using MW Irradiation KOH or t-BuOH/MW was used to remove the remainder of An agate mortar was charged with K2CO3 (5 g), ethyl TsCl [22]. In addition, to prepare methyl and ethyl tosylates, tosylate (20 mmol, 4.00 g), resorcinol (12 mmol, 1.32 g) methanol and ethanol were used in three folds compared to and DMF (1 ml). After mixing them by a pestle under a TsCl until the consumption of all of the TsCl was fume hood with safety cares, the mixture was transferred in investigated [23]. a pyrex beaker (200 ml) and put inside the microwave oven and exposed to irradiation (500 W) for 2 min. Upon Method C: Microwave Irradiation for the Synthesis completion the reaction, monitored by TLC (n-hexane/ of Bis-2-nitro and Bis-2-formylphenoxy Alkyl EtOAc, 4:1, V/V) the reaction vessel was cooled to room Ethers in DMF temperature and the mixture was stirred with potassium o-Nitrophenol (2 mmol, 0.27 g), dried K2CO3 (3 mmol, hydroxide solution (50%, 50 ml) to eliminate the excess of 0.40 g) and DMF (2 ml) were placed in a two necked resorcinol. Then, the product was extracted by n-hexane (3 reaction flask (25 ml) and placed inside the cavity of × 50 ml) and washed with H2O (2 × 50 ml) to omit the microwave instrument, operated at 90 ºC for 10 min. Then, remainder of DMF. The solvent was dried by anhydrous the diethylene glycol ditosylate (1 mmol, 0.414 g) was CaCl2 and evaporated by vacuo-rotary. The desired 1,3- added and the mixture was irradiated by MW for 75 min. diethoxybenzene was obtained in 95% yield, exclusively Water (10 ml) was added and extracted with diethyl ether (2 (Table 1, entry 16). × 30 ml). The organic layer was separated, dried with anhydrous Na2SO4 and evaporated in vacuum. The crude Method B: One-pot Preparation of Alkyl Aryl product was purified by short column chromatography (n- Ethers from Alcohols and Phenols hexane/EtOAc, 4:1) and obtained in 84% yield (Table 3, In a typical procedure, a mixture of 1-octanol (10 mmol, entry 2). 1.57 ml) and finely powdered KOH (50 mmol, 2.8 g) was vigorously grinded in an agate mortar for 5 min. Then, Method D: Large Scale Preparation of Bis-2- K2CO3 (5 g) and tosyl chloride (15 mmol, 2.86 g) were formylphenoxyalkyl Ethers added and grinded fully by a pestle. An exothermic reaction Diethylene glycol (50 mmol, 5.30 g) and dry K2CO3 (25 ensued, and was almost completed, immediately as g) were vigorously grinded for 5 min. Tosyl chloride (75 confirmed by TLC (n-hexane/ EtOAc, 4:1, V/V). To mmol, 14.30 g) was added and grinded for 10 min. MW eliminate the remaining TsCl, the finely powdered KOH (10 irradiation at 180 W accelerate the reaction rate 74 A Tandem Scalable Microwave-Assisted Williamson Alkyl Aryl Ether Synthesis/Org. Chem. Res., Vol. 3, No. 1, 73-85, March 2017. Table 1. Preparation of Alkyl Aryl Ethers by the Reaction of Phenols with Alkyl Tosylates on K2CO3 Using MW Irradiation Time Yieldf Entry Phenol Ether (min) (%) O CH3 7 1 4 96a 2 2 97a b 3 2 97 4 3 96a 5 2 97c d 6 2 93 d 7 2 96 8 2 90d 9 1 94b 10 1 92b 11 2 96c 75 Javaherian et al./Org. Chem. Res., Vol. 3, No. 1, 73-85, March 2017. Table 1. Continued 12 3 88c 13 2 95d 14 2 81e 15 2 91e O e 16 O 2 95 a b c d e f: power of MW irradiation: 200 W, 300 W, 400 W, 500 W, 1000 W, The reactions were carried out under solvent free condition (method A) and yields refer to isolated products. Table 2. Results of One-pot Preparation of Alkyl A ryl Ethers from Alcohols and Phenols Time Yield Entry Alcohol Ether (min) (%)c O CH3 7 a 1 CH3(CH2)6CH2OH 40 s 93 a 2 CH3(CH2)6CH2OH 50 s 94 3 1.5 92a 4 2 95b b 5 2 97 76 A Tandem Scalable Microwave-Assisted Williamson Alkyl Aryl Ether Synthesis/Org. Chem. Res., Vol. 3, No. 1, 73-85, March 2017. Table 2. Continued 6 2 90a 7 1 96b O 2 O O b 8 2 92 9 2 95b 10 2 93b b 11 2 96 12 2 90b b 13 CH3OH 2 96 14 2 85a a 15 CH3(CH2)6CH2OH 2 93 b 16 C2H5OH 2 94 17 2 95b a b c Power of MW irradiation: 1000 W, 500 W, The reactions were carried out under solvent free condition (method B) and yields refer to isolated product.

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