Ethers from alkoxides

Zirconium tetrachloride is instantly hydrolyzed in water to zirconium oxide dichloride octahydrate [13520-92-8]. Zirconium tetrachloride exchanges chlorine for 0x0 bonds in the reaction with hydroxylic ligands, forming alkoxides from alcohols (see Alkoxides, METAl). Zirconium tetrachloride combines with many Lewis bases such as dimethyl sulfoxide, phosphoms oxychloride and amines including ammonia, ethers, and ketones. The zirconium organometalLic compounds ate all derived from zirconium tetrachloride. 

A more recent synthesis for (14-9) takes quite a different course. The first step comprises the displacement of one of the halogens in 1,4-dibromobenzene by the alkoxide from A-2-hydroxyethylpyrrolidine (15-2) in the presence of 18-crown ether to afford (15-3). Condensation of the lithium salt from (15-3) with 6-methoxy-tetralone (15-4) followed by dehydration of the initially formed carbinol give the intermediate (15-5), which incorporates the important basic ether. Reaction of that compound with pridinium bromide perbromide leads to the displacement of the vinylic proton by halogen and the formation of bromide (15-6). Condensation of that product with phenylboronic acid in the presence of a tetrakistriphenyl-phosphine palladium catalyst leads to the coupling of the phenyl group by the formal displacement of bromine. The product (14-9) is then taken on to lasoxifene (14-11) as above [16]. 

Diethyl ether is prepared commercially by intermolecular dehydration of ethanol with sulfuric acid. The Williamson ether synthesis, another route to ethers, involves preparation of an alkoxide from an alcohol and a reactive metal, followed by an SN2 displacement between the alkoxide and an alkyl halide. 

The outcome of the reactions of la-lc initiated by depiotonation, is clearly dependent on the reaction medium and the applied base, i.e., the metal cation acting as the counter ion in the intermediate alkoxides. Changing the solvent, from ether to THF, the reaction of la-lc with lithium methyl at low temperature leads to trimethylsiloxybis(trimethylsilyl)silylalkanes lOa-lOc (Eq. 7). 

O-Alkylation of alcohols with alkylating agents is a practical method not only for the synthesis of unsymmetrical ethers (16), but also for protecting hydroxyl groups (17). The alkylation reactions are usually conducted under strongly basic conditions via the formation of alkoxides from alcohols. However, an alternative method performed under neutral conditions would be desirable for the conversion of alcohols that are sensitive to strong bases. 

Functionally substituted benzylic, allylic, and vinylic compounds containing alkoxides, esters, ethers, nitriles, or amides can be reacted with halosilanes under Barbier conditions using HMPT to yield C- and O-silylated products, 1,2- or 1,4-addition products, as well as reductive dimers. Radical and anionic intermediates are postulated, based on SET reactions from the metal, and multiple silated species can be obtained. The use of the TMSCl-Mg-HMPT system has been extensively investigated by Galas group [85] at the University of Bordeaux, and their work has greatly advanced the science of the Barbier reaction with silanes. 

Protection of primary hydroxyl groups. Sodium alkoxides (from sodium hydride) react with iodomethyl methyl sulfide at 0° in DME to form methyl-thiomethyl ethers (MTM ethers) in yields usually >86%. These ethers are stable to bases and nucleophiles (NaH, RLi, NaOR) and fairly stable to acid. Thus acetonide and THP protecting groups can be cleaved more easUy by acid than the MTM ether function. 

Williamson s synthesis A method for the preparation of mixed ethers by nucleophilic substitution. A haloalkane is refluxed with an alcoholic solution of sodium alkoxide (from sodium dissolved in alcohol) ... 

It is believed that a strong base such as KOH or potassium alkoxide will deprotonate the active hydrogen from the reactants, such as alcohols, thiols, amines, carboxylic acids, and phenols, to generate the nucleophiles that add to acetylene, as illustrated by the formation of vinyl ether from alcohol and acetylene. This can qualitatively explain the reactivity order among primary, secondary, and tertiary alcohols, without considering the steric hindrance. It is known that tertiary alcohol is less acidic than secondary and primary alcohol, therefore, less potassium f-butoxide will be formed than primary potassium alkoxide from KOH. ... 

The basic chemical principle behind sol-gel processing of metal alkoxides is the transformation of M—OR groups to M—O—M units via M—OH species. The direct formation of M—O—M units from metal alkoxides by ether cleavage is possible, but is only rarely observed under sol-gel conditions (see Section 7.10.3.3.1). Thus, the alkoxo ligands first have to be converted into hydroxo ligands (hydrolysis reaction), which can then undergo condensation reactions. 

Alkyl chloridites and dialkyl chloridites can be obtained simply by mixing trialkyl phosphites with phosphorus trichloride when an exchange process takes place (6.319). Fluoridites are not obtainable by these methods, but can be made by the action of SbF3 on the corresponding chloridite. Monochloridites can be prepared from dichloridites by adding the latter to a suspension of sodium alkoxide in ether (6.320). 

Oxygen.—Alcohols, Alkoxides, and Ethers. The chemistry of fluorinated alkenyl ethers and the conversion of fluoro-olefins into saturated ethers is dealt with in Chapter 2. Information culled from new patent literature... 

Lithium alkoxides play an important role in the oligomeric cyclization of dinitriles in the synthesis of phthalocyanines. The combination of potassium alkoxide-crown ether complex in a hydrocarbon solvent gives a very powerful catalyst for production of vinyl ethers from alcohols and acetylene (Eq. 7.9). ... 

Preparation.—Synthesis of acid-labile esters can be achieved by treatment of the corresponding lithium alkoxide, from the alcohol and n-butyl-lithium, with an acid chloride t-butyl pivalate can be obtained in 64% yield by this procedure. Hindered acids are esterified by triethyloxonium fluoroborate in the presence of ethyl di-isopropylamine. The use of boron trifluoride etherate-alcohol is recommended as a mild, efficient esterification method, as is the employment of alkyl t-butyl ethers, which react with carboxylic acids under acid catalysis to give the alkyl ester, isobutene, and water, no free alcohol being ever present. 

The reactants in both reactions are a haloaUtane and the conjugate base of an alcohol, an alkoxide. The ether has two different alkyl groups bonded to oxygen, one from the alkoxide and the other from the haloalkane. 

In general, the metal alkoxide or any other suitable precursor is dissolved in an alcohol or any other suitable organic solvent (Figure 6.2). A solution of anhydrous hydrogen fluoride in, for example, alcohol or ether is added in about stoichiometric amounts to the precursor solution, resulting in a clear, translucent sol, which may become a gel, depending on concentration, type of precursor, and solvent (step 3). Varying the alkoxide from methoxide over ethoxide. 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

Secondary and tertiary alkyl halides are not suitable because they react with alkox ide bases by E2 elimination rather than by 8 2 substitution Whether the alkoxide base IS primary secondary or tertiary is much less important than the nature of the alkyl halide Thus benzyl isopropyl ether is prepared m high yield from benzyl chloride a pri mary chloride that is incapable of undergoing elimination and sodium isopropoxide... 

Both reactants m the Williamson ether synthesis usually originate m alcohol pre cursors Sodium and potassium alkoxides are prepared by reaction of an alcohol with the appropriate metal and alkyl halides are most commonly made from alcohols by reaction with a hydrogen halide (Section 4 7) thionyl chloride (Section 4 13) or phosphorus tri bromide (Section 4 13) Alternatively alkyl p toluenesulfonates may be used m place of alkyl halides alkyl p toluenesulfonates are also prepared from alcohols as their imme diate precursors (Section 8 14)... 

Next in what amounts to an intramolecular Williamson ether synthesis the alkoxide oxygen attacks the carbon that bears the halide leaving group giving an epoxide As m other nucleophilic substitutions the nucleophile approaches carbon from the side oppo site the bond to the leaving group... 

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