Preparation of Aryl Ethers

Aryl ethers are best prepared by the Williamson method (Section 16.6). Alkylation of the hydroxyl oxygen of a phenol takes place readily when a phenoxide anion reacts with an alkyl halide. 

As the synthesis is normally performed, a solution of the phenol and alkyl halide is simply heated in the presence of a suitable base such as potassium carbonate  

This is an example of an 5 2 reaction in a polar aprotic solvent. 

The alkyl halide must be one that reacts readily in an Sn2 process. Thus, methyl and primary alkyl halides are the most effective alkylating agents. Elimination becomes competitive with substitution when secondary alkyl halides are used and is the only reaction observed with tertiary alkyl halides. 

The reaction between an alkoxide ion and an aryl halide can be used to prepare alkyl aryl ethers only when the aryl halide is one that reacts rapidly by the addition-elimination mechanism of nucleophilic aromatic substitution (Section 23.6). 

This is an exampie of an Sn2 reaction in a poiar aprotic soivent. 

PROBLEM 24.8 Reaction of phenol with 1,2-epoxypropane in aqueous sodium hydroxide at 150°C gives a single product, C9H12O2, in 90% yield. Suggest a reasonable structure for this compound. 

The aryl ethers shown here are intermediates that have been used to make pharmaceuticals. In each case, provide the structures of the phenol and the alkyl halide from which these compounds can be synthesized. 

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Lizarzabum, M.E. and Shuttleworth, S.J. (2003) Convenient preparation of aryl ether derivatives using a sequence of functionalized pol3miers. Tetrahedron Letters, 44, 4873 876. 

Solid-supported triphenylphosphine, first reported by Havens et al. in 1983 for an esterification reaction, has found extensive applications in Mitsunobu chemistry. For example, the preparation of aryl ethers from amino alcohols has been carried out interestingly, addition of triethylamine led to better conversion in some cases. " More recently, Pelletier et al. prepared a series of primary amines by reaction of a primary alcohol in the presence of (Boc)2NH, TBAD and solid-supported TPP. Typical reported yields were in excess o l5% ... 

Arenethiols are important intermediates in chemical synthesis. While there are numerous reactions to introduce this functionality starting from aryl halides or phenols, most of these transformations require drastic reaction conditions and tolerate few if any functionalities. Despite the fact that in the last few years the efficiency of palladium-catalyzed cross-coupling reactions for the preparation of aryl ethers and aniline derivatives has improved greatly (see 5.1 and 5.2), analogous methods for the formation of aryl sulfides and especially arenethiols have lagged behind. The first report of a mild palladium-catalyzed synthesis of arenethiols came from Rane et followed by reports from a Zeneca Pharma group and a Merck group (Scheme 5-160). ... 

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