Unsymmetrical ethers

Although the yields are often poor, especially for halides other than primary alkyl halides, it remains a valuable method for synthesizing unsymmetrical ethers. 

Ethers are described as symmetrical or unsymmetrical depending on whether the two groups bonded to oxygen are the same or different Unsymmetrical ethers are also called... 

The following section describes a versatile method for preparing either symmetri cal or unsymmetrical ethers that is based on the principles of bimolecular nucleophilic substitution... 

Unsymmetric ethers, ROR", react with HI by a protonation-substitution mechanism that can lead to two different product combinations. 

Interestingly, some unsymmetric ethers undergo selective cleavage and give only one of the two possible product combinations. 

This reaction, which is named after W. Williamson, is the most important method for the synthesis of unsymmetrical ethers 3. For this purpose an alkoxide or phenoxide 1 is reacted with an alkyl halide 2 (with R = alkyl, allyl or benzyl). Symmetrical ethers can of course also be prepared by this route, but are accessible by other routes as well. 

Because the Williamson synthesis is an S 2 reaction, it is subject to all the usual constraints, as discussed in Section 11.2. Primary halides and tosylates work best because competitive E2 elimination can occur with more hindered substrates. Unsymmetrical ethers should therefore be synthesized by reaction between the more hindered alkoxide partner and less hindered halide partner rather than vice versa. For example, terf-butyl methyl ether, a substance used in the 1990s as an octane booster in gasoline, is best prepared by reaction of tert-butoxide ion. with iodomethane rather than by reaction of methoxide ion with 2-chloro-2-methylpropane. 

The direction of cleavage in unsymmetrical ethers is determined by the relative ease of O-R bond breaking by either SN2 (methyl, benzyl) or SW1 (r-butyl) processes. As trimethylsilyl iodide is rather expensive, alternative procedures that generate the reagent in situ have been devised. 

This method is not useful for the preparation of unsymmetrical ethers from 1° alcohols because the reaction leads to a mixture of products ... 

When alcohols are added to the reaction mixture, unsymmetrical ether products may be obtained. Starting with a mixture of aldehydes can also give rise to the formation of unsymmetrical ethers. These ether products are formed under conditions different from those used in the formation of ethers directly from alcohols. Thus, it is postulated that the reaction sequence that leads from the carbonyl substrate to the ether involves the intermediate formation of hemiacetals, acetals, or their protonated forms and alkoxycarbenium ions, which are intercepted and reduced to the final ether products by the organosilicon hydrides present in the reaction mix. The probable mechanistic scheme that is followed when Brpnsted acids are present is outlined in Scheme 2.311-327 328... 

Unsymmetrical ethers may be produced from the acid-promoted reactions of aldehydes and organosilicon hydrides when alcohols are introduced into the reaction medium (Eq. 173).327,328 An orthoester can be used in place of the alcohol in this transformation.327 335 A cyclic version of this conversion is reported.336 Treatment of a mixture of benzaldehyde and a 10 mol% excess of triethylsilane with methanol and sulfuric, trifluoroacetic, or trichloroacetic acid produces benzyl methyl ether in 85-87% yields.328 Changing the alcohol to ethanol, 1-propanol, 2-propanol, or 1-heptanol gives the corresponding unsymmetrical benzyl alkyl ethers in 45-87% yield with little or no side products.328 A notable exception is the tertiary alcohol 2-methyl-2-propanol, which requires 24 hours.328 1-Heptanal gives an 87% yield of //-lie ply I methyl ether with added methanol and a 49% yield of benzyl n-heptyl ether with added benzyl alcohol under similar conditions.328... 

Superior yields of ethers from aldehydes are obtained by the use of several other electrophilic species. The addition of 5 mol% of trityl perchlorate to a mixture of triethylsilane and 3-phenylpropanal in dichloromethane at 0° produces an 83% yield of bis-(3-phenylpropyl) ether within 10 minutes (Eq. 176),329 Reductive polycondensation of isophthalaldehyde occurs with two equivalents of triethylsilane in the presence of 10 mol% of trityl perchlorate to give 40-72% yields of polyether with average molecular weights ranging from 6,500 to 11,400 daltons (Eq. 177).337 Addition of one equivalent of an alkoxytrimethylsilane to the reaction mixture produces unsymmetrical ethers in good to excellent yields. Thus, a mixture of (ii)-cinnamaldehyde, 3-phenylpropoxytrimethylsilane, and triethylsilane in dichloromethane reacts under the influence of a catalytic amount of trityl perchlorate to give the unsymmetrical ether in 88% yield (Eq. 178).329... 

The formation of unsymmetrical ethers from the reduction of aldehydes in the presence of tetrahydropyran (THP) ethers is reported (Eq. 182).340... 

Equivalent amounts of aldehydes and alkoxytrimethylsilanes react to form unsymmetrical ethers in near quantitative yields in the presence of either trimethylsilane or triethylsilane and catalytic amounts (ca. 10 mol%) of TMSI in dichloromethane.329,333,334,341 The procedure is particularly convenient experimentally when trimethylsilane is used with TMSI because the catalyst provides its own color indicator for the reduction step (color change from deep violet to vivid red-gold) and the only silicon-containing product following aqueous workup is the volatile hexamethyldisiloxane (bp 99-100°). It is possible to introduce trimethylsilane (bp 7°) either as a previously prepared solution in dichloromethane or by bubbling it directly into the reaction mixture. Cyclohexyloxytrimethylsilane and n-butanal react by this method to give a 93% isolated yield of n-butyl cyclohexyl ether (Eq. 183).334... 

The organosilane reduction of ketones in the presence of alcohols provides an excellent route to unsymmetrical ethers. The reaction of cyclohexanone with ethanol and Et3SiH/TFA gives cyclohexyl ethyl ether in good yield.327,328 The... 

Ethyl Benzyl Ether [Brpnsted Acid Promoted Reduction of an Aldehyde to an Unsymmetrical Ether].327 To a cooled mixture of benzaldehyde (4.3 g, 41 mmol) and absolute ethanol (3.7 g, 80 mmol) was added trichloroacetic acid (18.2 g, 111 mmol). Et3SiH (6.96 g, 60 mmol) was then added dropwise with stirring while the mixture was maintained at 50-60°. After 4 hours, the reaction mixture was diluted with water, neutralized with aqueous NaHC03 solution, and extracted with Et20. The dried ether extract was distilled and the 170-190° fraction was collected. Distillation from sodium gave ethyl benzyl ether 4.8 g (90%) bp 187-189°. 

Heptyl 3-Phenylpropyl Ether [Electrogenerated Acid-Promoted Reduction of an Aldehyde to an Unsymmetrical Ether].333 A mixture of 1-heptanal (1.0 mmol), 3-phenylpropoxytrimethylsilane (1.2 mmol), tetra-n-butylammonium perchlorate (0.1 mmol), and lithium perchlorate (0.1 mmol) was dissolved in CH2CI2 (3 mL) in an undivided cell. The mixture was electrolyzed under constant current (1.67 mA cm-2) with platinum electrodes at ambient temperature. After 5 minutes, dimethylphenylsilane (1.2 mmol) was added drop-wise and the electrolysis was continued (0.06 Faraday/mol). After completion of the reaction, one drop of Et3N was added and the solution was concentrated. The residue was chromatographed on Si02 to give 1-heptyl 3-phenylpropyl... 

Cyclohexyl ethyl ether [TMSI-catalyzed ketone-unsymmetrical ether reduction], 124... 

A similar strategy has been employed in the synthesis of a dihydropyran required to achieve the synthesis of (—)-lanlimalide (Scheme 23). Thns, ally-lation of the secondary alcohol resnlting from a methallylation of 3-tri-n-butylstannylacrolein provided unsymmetrical ether 182, which is closed to a pyran with a ring-closing metathesis using Schrock s molybdennm catalyst. 

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