Ethyl phenyl ether, synthesis

How would you prepare ethyl phenyl ether Use whichever method you think is more appropriate, the Williamson synthesis or the alkoxymercuration reaction. 

Draw the target ether, identify the two groups attached to oxygen, and recall the limitations of the two methods for preparing ethers. The Williamson synthesis uses an Sn2 reaction and requires that one of the two groups attached to oxygen be either secondary or (preferably) primary. The alkoxymercura-tion reaction requires that one of the two groups come from an alkene pis-cursor. Ethyl phenyl ether could be made by either method. 

Trimethylanisole reacts with excess chlorosulfonic acid to give 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride this compound is used as a reagent for the protection of amino groups in peptide synthesis. Phenetole (ethyl phenyl ether, 187 R = Et), by reaction with chlorosulfonic acid (two equivalents) in chloroform yields the 4-sulfonyl chloride ° which is used in the preparation of heat sensitive recording materials. ... 

Examples of the preparation of alkyl benzyl ethers by the Williamson synthesis are included in Section 5.6.2, p. 583. An example of an alkyl phenyl ether is provided by the synthesis of phenacetin (Expt 6.109) where p-aminophenol is first converted into its Af-acetyl derivative by reaction with slightly more than one equivalent of acetic anhydride. Treatment of the product with ethanolic sodium ethoxide solution followed by ethyl iodide then yields the ethyl ether of AT-acetyl-p-phenetidine (phenacetin). This compound is biologically active and has been widely employed for example as an antipyretic and analgesic however, owing to undesirable side reactions, its use is now restricted. 

An interesting application of the Fujiwara-Moritani/oxidative Heck reaction for the synthesis of benzo furans was recently reported by the Stoltz lab [31]. A variety of allyl phenyl ethers (all containing electron-rich aryl components) react with 10 mol% palladium acetate, 20 mol% ethyl nicotinate, 20 mol% sodium acetate, and one equivalent of benzoquinone at 100°C to provide benzofurans in 52-79% yield (e.g. 16—>17). The mechanism of this transformation begins with arene palladation of Pd(II) followed by olefin insertion, p-hydrogen elimination, and olefin isomerization to the thermodynamically favored benzofuran product. The resulting Pd(0) species is then oxidized to Pd(ll) thus regenerating the active catalyst. 

PPG-2 methyl ether PPG-3 methyl ether Propylene glycol phenyl ether Tetrabromoethane Tetrahydronaphthalene Tripropylene glycol ethyl ether solvent, Grignard reactions Tetrahydrofuran solvent, Grignard synthesis Dibutyl ether... 

Synthesis by Selective Cationic Pofymerization of 2>(3 Phenyl-2 -norltornadiene>2-carl)onylo gr)ethyl Vinyl Ether and Photochemical Reaction of the Resulting Pofymers... 

Synthesis of 2-(3-[(Phenyl)carbamoyI]-2,5-norbomadiene-2-cariMmyIo ty) ethyl Vinyl Ether (PCNVE)... 

Nishikubo, T., Kameyama, A., Kishi, K., Kawashima, T., Fujiwara, T., and Hijikata, C., Synthesis of new photoresponsive polymers bearing norbomadiene moieties by selective cationic polymerization of 2- [ [ (3-phenyl-2,5-norbomadienyl)-2-carbonyl] oxy] ethyl vinyl ether and photochemical reaction of the resulting polymers. Macromolecules, 25,4469-4475,1992. 

A mixture of 23 parts of the ethyl ester of 4 phenylisonipecotic acid and 15 parts of 2,2-diphenyl-4-bromobutyronitrile in 19 parts of xylene is heated for 24 hours at 100°-120°C and then cooled and filtered to remove the precipitate of the hydrobromide of the ethyl ester of 4-phenylisonipecotic acid. The filtrate is then extracted with dilute hydrochloric acid and the extract is rendered alkaline by addition of concentrated aqueous potassium hydroxide and extracted with ether. This ether extract is treated with gaseous hydrogen chloride. The resulting precipitate is collected on a filter. The hydrochloride of the ethyl ester of 2,2 diphenyl-4-(4 -carboxy-4 -phenyl-1 -piperidino) butyronitrile thus obtained melts at about 220.5-222°C. See Meperidine hydrochloride for synthesis of 4-phenyl-isonipecotic acid ethyl ester. 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

Remark. The procedure described in Section 2.8.3 for the synthesis of -V-phenyl imidothioesters gave poor results in the case of methylmagnesium iodide, mainly because of low stability of its addition product to phenyl isothiocyanate. A good yield could be secured by running the reaction at a lower temperature in ether as the solvent and addition of HMPA in the methylation step. Filtration on a very short column of silica (eluent petroleum ether/ethyl acetate 97.5 2.5) afforded a quite pure product in a 79% yield. 

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