7-Halo ethers, preparation

Another method for the synthesis of epoxides is through the use of halo-hydrins, prepared by electrophilic addition of HO—X to alkenes (Section 7.3). When halohydrins are treated with base, HX is eliminated and an epoxide is produced by an intramolecular Williamson ether synthesis. That is, the nucleophilic alkoxide ion and the electrophilic alkyl halide are in the same molecule. 

This procedure illustrates a general method for the stereoselective synthesis of ( P)-disubstitnted alkenyl alcohols. The reductive elimination of cyclic /3-halo-ethers with metals was first introduced by Paul3 and one example, the conversion of tetrahydrofurfuryl chloride [2-(chloromethyl)tetrahydrofuran] to 4-penten-l-ol, is described in an earlier volume of this series.4 In 1947 Paul and Riobe5 prepared 4-nonen-l-ol by this method, and the general method has subsequently been applied to obtain alkenyl alcohols with other substitution patterns.2,6-8 (I )-4-Hexen-l-ol has been prepared by this method9 and in lower yield by an analogous reaction with 3-bromo-2-methyltetra-hydropyran.10... 

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. °... 

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... 

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). 

Vinyl ethers have also been prepared by addition of alkoxides to acetylene,6 7 6 elimination from halo ethers and related precursors,6 8 and vinyl exchange reactions.6 Reaction of an electrophilic tungsten carbenoid with methylene phosphorane or diazomethane also produces vinyl ethers.9 Enol ethers have resulted from the reaction of some tantalum and niobium carbenoids with esters,10 and the reaction of phosphoranes with electrophilic esters.4... 

The method has been used for the preparation of dihalides, e.g., 1,9-dichlorononane (93%) unsaturated halides, e.g., 11-undecylenyl chloride (83%) halo ethers, e.g., /3-ethoxyethyl chloride (80%) halo ketones, e.g., desyl chloride (79%) halo esters, e.g, methyl a-chloropropionate (71%) halo cyanides, e.g., phenylchloroacetonitrile (80%) and aminoalkyl halides,An interesting isomerisation has been observed in liberating 2-diethylamino-l-chloropropane from its hydrochloride salt l-diethylamino-2-chloropropane is formed. ... 

On the other hand, if diethyl ether is treated at —20° or below with one equivalent of chlorine, a-chloroethyl ethyl ether is formed in 42% yield. Further chlorination at this low temperature leads to a,a -di-chlorodiethyl ether in 57% yield, the second chlorine atom entering a new alpha position in preference to an alpha position already substituted. The extension of this new technique to higher ethers is under way. Other methods are available for the preparation of a- and /3-halo ethers (see Chapter 6). 

Halo ethers are prepared by adding an alcoholic solution of the sodium alkoxide to the polymethylene halide, X(CHj) X, in anhydrous ether or benzene, as illustrated by the preparation of l-bromo-6-methoxyhexane (47%). In a somewhat different manner, an aromatic halo ether such as y-phenoxypropyl bromide is synthesized by the action of phenol and the dihalide in the presence of hot aqueous sodium hydroxide (85%). The syntheses of o- and p-chlorophenyl phenyl ethers have been successfully accomplished by the Ullmann procedure (40-55%), whereas chlorination of diphenyl ether yields an inseparable mixture of isomers. ... 

The reduction of diazonium salts by sodium sulfite forms monosub-stituted arylhydrazines. An improved procedure for the synthesis of phenylhydrazine in 84% yield is typical. Arylhydrazine salts substituted in the nucleus with halo," ether, carboxyl, or nitro groups have been prepared. The free bases are liberated from the salts by the action of aqueous sodium hydroxide or sodium acetate. 

Two techniques are commonly used in the preparation of olefinic ethers from halo ethers. The first involves heating a /5-halo ether with fused or powdered potassium hydroxide. This method is typified by the conversion of -phenoxyethyl bromide to phenyl vinyl ether (69%) and, /5 -dichlorodiethyl ether to divinyl ether (61%). In the latter case, yields are improved in the presence of ammonia gas. In the second procedure, an aliphatic or aromatic chloro ether is heated with pyridine to 115°. This method is of value in the preparation of several methoxystyrenes. Chloroalkylation of the aromatic ether is followed by dehydrohalogenation. 

RC = CCH,X — RCX = C==CH,. /S.y- and 7,S-Acetylenic alcohols can be transformed to the halides in better yields by an alternative procedure, which consists in their esterification with p-toluenesulfonyl chloride and subsequent cleavage of the ester by the action of sodium iodide, lithium chloride, or calcium bromide in an appropriate solvent (60-90%). Halo ethers are prepared by the action of phosphorus tribromide on hydroxy ethers, as in the preparation of /3-ethoxyethyl bromide (66%). In a similar manner, /3-halo esters have been prepared without appreciable dehydration of the /3-hydroxy ester (40-60%). The reaction of cyanohydrins leads to a-halo nitriles. Treatment of 2-nitro-l-propanol with phosphorus pentachloride gives l-chloro-2-nitropropane (47%). ... 

Many other groups may be present in the alcohol or phenol during alkylation. Dimethyl sulfate and chlorohydrins give chloro ethers. Halo ethers are also prepared by the action of this reagent on halogenated phenols, e.g., w-bromoanisole (91%)- Phenolic aldehydes are converted in excellent yields to alkoxy aldehydes with dimethyl sulfate or alkyl p-toluenesulfonates. The conversion of a phenolic ketone to an alkoxy ketone is illustrated by the preparation of p-methoxypropiophenone (88%). Phenolic acids, esters, and cyanides, and nitrophenols respond favorably to this method for methylation. The sodium salt of mandelic acid, C H, CHOHCOOH, is methylated with dimethyl sulfate to furnish, after acidification, a-methoxyphenylacetic acid (42%). ... 

The catalyzed reaction of enol ethers with carbonyl compounds (Scheme 1) has become an important reaction in synthesis. Compared to the metal enolate reactions (Part 1, Volume 2), the catalyz enol ether reactions offer the following distinct differences. Enol ethers are often isolable, stable covalent compounds, whereas the metal enolates are usually generated and used in situ. Under Lewis acid catalyzed conditions, a number of functional equivalents such as acetals, orthoesters, thioacetals, a-halo ethers and sulfides can participate as the electrophilic components, whereas many of them are normally unreactive towards metal enolates. In synthesis, enol ether reactions now rival and complement the enolate reactions in usefulness. Enol silyl ethers are particularly useful because of their ease of preparation, their reasonable reactivity and the mildness of the desilylation process. 

Such reactions have preparative value when the halo ether is easily accessible by halogenation of an ether. For example, 2,3-dichlorodioxan and ethanol yield the cyclic acetal of glyoxal 935 and cyclic acetals of 2-chloro-4-hydroxy-butyraldehyde are formed from 2,3-dichlorotetrahydrofuran and alcohols 936, 937... 

Alkylation by -halo ethers is of preparative interest only in special cases and is often accompanied by side reactions, e.g., loss of hydrogen halide. The subject has been reviewed several times.504... 

This method of reaction is also applicable to the preparation of hydroxy nitriles (from chlorohydrins, yields about 80%)452 and a-alkoxy nitriles (from -halo ethers and copper cyanide, yields 55-80%).453... 

Dioxetanes. These unstable compounds have been isolated from the reactions of alkenes and singlet oxygen (5,487-488). Kopecky et al have reported a nonphotochemical route to 1,2-dioxetanes from j3-halo hydroperoxides, prepared by reaction in ether of an alkene, 98% H2O2, and 1,3-dibromo- or... 

E)-Disttbstitttted alkenyl alcohols (4, 437). Full details for the preparation of (E)-4-hcxcne-l-ol by fragmentation of cyclic 8-halo ethers with sodium have been published. References to other examples of this cleavage are cited. ... 

The preparation of linear monothioacetals or dithioacetals may be accomplished by either the reaction of cysteine hydrochloride with the appropriate a-halo ether or sulphide in methanol or better by the base catalyzed alkylation of cysteine in liquid ammonia. Young and associates [11, 115] have utilized alkylation reactions of this type to prepare several... 

The reaction is also applicable to both primary and secondary halides and to a-halo ethers [16]. Iodide ions catalyze the replacement of chlorine. Tertiary halides and alicyclic halides tend to form olefins or decomposition products. The preparation of pentanonitrile using dimediyl sulfoxide is representative of the procedure although dimeth-ylformamide has also been used [17]. 

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