Ethers a-halo

In general the Stork reaction gives moderate yields with simple alkyl halides better yields of alkylated product are obtained with more electrophilic reactants such like allylic, benzylic or propargylic halides or an a-halo ether, a-halo ester or a-halo ketone. An example is the reaction of 1-pyrrolidino-l-cyclohexene 6 with allyl bromide, followed by aqueous acidic workup, to yield 2-allylcyclohexanone ... 

The method is quite useful for particularly active alkyl halides such as allylic, benzylic, and propargylic halides, and for a-halo ethers and esters, but is not very serviceable for ordinary primary and secondary halides. Tertiary halides do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and elimination predominates. The reaction can also be applied to activated aryl halides (such as 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, " and to activated alkenes such as acrylonitrile. The latter is a Michael type reaction (p. 976) with respect to the alkene. 

In a related process, a-halo ethers can be prepared by treatment of aldehydes and ketones with an alcohol and HX. The reaction is applicable to aliphatic aldehydes and ketones and to primary and secondary alcohols. The addition of HX to an aldehyde or ketone gives tx-halo alcohols, which are usually unstable, though exceptions are known, especially with perfluoro and perchloro species. °... 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allyl and benzyl halides, a-halo esters, a-halo ethers, and a-halo ketones are the most successful alkylating agents. The use of enamines for selective alkylation has largely been supplanted by the methods for kinetic enolate formation described in Section 1.2. 

There are very few precedents for the reaction of cyclic a-halo ethers with carbanions. Zelinski and coworkers114 and Schudel and Rice115 reported the preparation of diethyl DL-tetrahydropyran-2-ylmalonate (137) by treatment of 2-bromo- or 2-chloro-tetrahydropyran (136) with diethyl sodiomalonate. The product was subsequently converted into the malonic and acetic acid derivatives, 138 and 139, respectively. The same sequence has also been reported by other workers.116... 

Reaction of Metallated Acetylenes with Alkyl Halides, a-Halo-ethers, Epoxides and Alkyl Orthoformates... 

Iron-acyl enolates, such as 2, prepared by x-deprotonation of the corresponding acyl complexes with lithium amides or alkyllithiums, are nearly always generated as fs-enolates which suffer stereoselective alkylation while existing as the crmt-conformer which places the carbon monoxide oxygen anti to the enolate oxygen (see Section 1.1.1.3.4.1.). These enolates react readily with strong electrophiles, such as primary iodoalkanes, primary alkyl sulfonates, 3-bromopropenes, (bromomethyl)benzenes and 3-bromopropynes, a-halo ethers and a-halo carbonyl compounds (Houben-Weyl, Volume 13/9 a, p 413) (see Table 6 for examples). 

Cl—H, ROH I Cl—C—OR I acidic catalysts Section 16-4D, synthesis of a-halo ethers... 

The mechanism of this reaction has been investigated in some detail. RX must be an activated halide, such as a benzyl halide, a-halo ether, or a 1,1-dihalocarbon where at least one of the halides is Br or L Simple halocarbons do not react, nor does methylene chloride. Reaction with chloroform is slow, while reaction with carbon tetrachloride is instantaneous at room temperature. The (pseudo) first-order rate constant is linearly correlated to the polarographic reduction potential of the halide thus electron transfer from (38) to RX (equation 57) is the rate-determining step, followed by rapid cleavage of the RX radical anion into R and X . 

Treatment of a-halo ethers with metallic cyanides such as cuprous, mercuric, or silver cyanides gives the corresponding cyano ethers the alkali cyanides are without effect. Very little of the corresponding isonitriles are encountered despite the fact that these compounds often result from the interaction of heavy-metal cyanides and alkyl halides. Generally, cuprous cyanide, the most commonly used reagent, is suspended in dry anhydrous ether or dry benzene and treated with the halo ether under gentle reflux (55-80%). 

The a-position of an ether is susceptible to attack by free radicals and, in certain circumstances, by halogens. Ethers are slowly oxidized by the oxygen from air to form peroxides- This can be a hazard in stored bottles of ethers, particularly with the higher ethers such as di-isopropyl ether. These peroxides may be destroyed by treatment with iron(IT) sulfate. Chlorine reacts with ethers, particularly in sunlight. These a-halo ethers then decompose to the aldehyde and an alcohol. 

Mechanistically most of these transformations correspond to 5N2-type substitutions chiral substrates react with inversion. In certain cases, however, azides may also be obtained under 5n1 condi-tions." " " Some di- and tri-arylmethanols for instance (Scheme 32) react with HN3 in the presence of trichloroacetic acid via the corresponding carbenium ions. Sulfuric acid seems to be inferior for these transformations." " Under highly acidic conditions the intermediate (20) obviously tends to decompose with the elimination of nitrogen (c/. Schmidt reaction "). SnI substitution is also highly probable in the reaction of a-halo ethers and sulfides with azide ions." " In some cases even SRNl-type substitution was observed for the halogen/azide exchange." ... 

Most commonly, oxocarbenium ions (94) are formed from acetals (93), by treatment with either Brpnsted or Lewis acids (Scheme 44). In a similar way, a-halo ethers (95) have also been used as potent sources of oxocarbenium ions. ... 

A major drawback in the use of homocuprates, RaCuLi, is that one of the alkenyl or aryl groups can often be wasted clearly, however, this is not a serious problem if the cuprate is derived from a simple or-ganolithium. With reactive electrophiles such as allylic halides or a-halo ethers, both organic ligands are alkylated in the presence of 1 equiv. of HMPA, but with less reactive alkyl halides, at least 3 equiv. of (EtOlaP are required to stabilize the intermediate cuprate species during the much slower transfer of the second alkenyl ligand. ... 

Pudovik, A.N., Nikitina. V.L, and Kurguzova, A.M., Reactions of organophosphorus compounds containing active methylene groups with methyl (l-chlorovinyl ketone and a-halo ethers, Zh. Obshch. Khim., 40, 291, 1970 J. Gen. Chem. USSR (Engl. Transl.), 40, 261, 1970. 

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