A-Haloethers

The anomeric effect is also present in acyclic systems and stabilizes conformations that allow antiperiplanar (ap) alignment of the C—X bond with a lone-pair orbital of the heteroatom. Anomeric effects are prominent in determining the conformation of acetals and a-alkoxyamines, as well as a-haloethers. MO calculations (4-3IG) have found 4kcal/mol as the difference between the two conformations shown below for methoxy-methyl chloride. ... 

In contrast to hydrogen-type ethers, a-haloethers, both linear and cyclic, are relatively easily cleaved by anhydrous hydrogen fluoride. Bis( 1,1 -difluoroalkyl) ethers are converted to 1,1,1 -trifluoroalkanes and alkanoyl fluorides The cleavage temperature depends on the substituents present ethers having no electronegative substituents other than a-fluorines are readily cleaved below 20 °C, 3-halo-1,1-di fluoroethers require approximately 70 °C, but 2-halo-1,1-difluoroethers are prac tically resistant toward hydrogen fluoride [/I (equation 1)... 

Van Duuren BL, Goldschmidt BM, Langseth L, et al a-Haloethers A new type of alkylating carcinogen. Arch Environ Health 16 472-476, 1968... 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allylic and benzylic halides, a-haloesters, a-haloethers, and a-haloketones are the most successful alkylating agents. Some typical examples of enamine alkylation reactions are shown in Scheme 1.10. 

Reactions of polar organometallic and Grignard reagents with a-haloethers generally proceed much more easily than the familiar SN2 displacements with alkyl halides. This may be explained by the large extent of Sjql character due to the ionization ... 

The support originally used for solid-phase synthesis was partially chloromethy-lated cross-linked polystyrene, which was prepared by chloromethylation of cross-linked polystyrene with chloromethyl methyl ether and tin(IV) chloride [1-3] or zinc chloride [4] (Figure 6.1). Haloalkylations of this type are usually only used for the functionalization of supports, and not for selective transformation of support-bound intermediates. Because of the mutagenicity of a-haloethers, other methods have been developed for the preparation of chloromethyl polystyrene. These include the chlorination of methoxymethyl polystyrene (Figure 6.1 [5]), the use of a mixture of dimethoxymethane, sulfuryl chloride, and chlorosulfonic acid instead of chloromethyl methyl ether [6], the chlorination of hydroxymethyl polystyrene [7], and the chlorination of cross-linked 4-methylstyrene-styrene copolymer with sodium hypochlorite [8], sulfuryl chloride [8], or cobalt(III) acetate/lithium chloride [9] (Figure 6.1, Table 6.1). 

Alkylcarboxonium ions may be synthesized easily by the dehalogenation of a-haloethers. In Magic Acid, first the oxygen is protonated to oxonium ion 319, which, upon increasing temperature, decomposes to yield alkylcarboxonium ion 320 [Eq. (3.87)].624 In a similar manner, protonation of a-alkoxyacetic chlorides625 or acids626 also leads to carboxonium ions. The latter approach was used to generate cyclic alkylcarboxonium ion 321 [Eq. (3.88)]. 

For instance, the rate of SN2 reaction is greatly enhanced in a-haloethers 62 and in a-haloketones 63. This enhancement should however occur only when the oxygen atom in 62 has an electron pair anti peri planar to the C — Cl bond (cf 64+ 65). Similarly, in an o-haloketone the it system of the carbonyl group must be parallel to the C —Cl bond (cf, 66 67) (20). 

Treatment of 4-methoxy-27/-pyran-2-one with a haloether in the presence of TiCR provided 3-formyl-4-methoxy-2//-pyran-2-one, which is a useful synthon in natural products synthesis (Equation 19) < 1998JCXI8748, 2001COR571>. 

Electrophilic substitution at C-3 and C-5 of pyran-2-one, 198, has been achieved by treatment of pyran-2-one with a haloether in the presence of Zn/HCl <1992C457, 2001COR571 >. 3,5-Disubstituted alkyl pyran-2-ones were the major products of this reaction (Equation 20). 

HC1 is introduced at 0 C into a stirred mixture of ethanol (0.50 mol) and paraformaldehyde (15 g) until copious fumes escape from the solution. Stirring is stopped and the flask is placed in a bath at -78 C. The clear liquid is decanted from the crust of the bottom of the flask and transferred into a 1 -1 flask, which is placed in a bath at -20 C. The dissolved HC1 is then removed by evacuation (water aspirator). Since a-haloethers are suspected of being carcinogens, care should be taken when working with them. 

A convenient, general and efficient (96% yield) synthesis of primary a -alkoxyorgano-stannanes from stannylanions and a-haloethers has been reported (equation 101 )28. 

Alkynylmagnesium halides are less basic than the alkali metal acetylides and therefore can be applied to sensitive alkylating agents. In contrast to the alkali metal acetylides they do not react with saturated primary halides. On the other hand, they do react with allylic, propargylic and benzylic halides, but only in the presence of cuprous chloride catalysts. They also react with a-haloethers (e.g. equation 136)" . 

Reactions of a-haloethers in aqueous medium has been reviewed recently . The reactions in water are extremely rapid and in general precise kinetic data is not available. For example, it is estimated that methyl chloromethyl ether undergoes hydrolysis 10 times faster than n-propyl chloride . The rapidity of the reactions of a-haloethers is attributed to resonance stabilization of the transition state according to the structures... 

The crucial step in this mechanism is the second one in which the a-haloether moiety 115 solvolyzes to give an oxocarbocation. In order to obtain the ionic bicyclobutane this step has to compete effectively with both protonation of the carbanion and the 1,3-elimination reaction. By using oxygen nucleophiles, e.g. MeO", EtO" and CF3CH2O", in pro tic solvents, the rate of these three reactions was found to decrease in the order solvolysis > elimination > protonation. Although an apolar medium is expected to enhance the elimination reaction and to slow down the solvolytic step, it was shown that for MeO" in THF, the ionic bicyclobutane route still prevails. ... 

Gross, H., Freiberg, J., and CostiseUa, B., a-Haloethers. Part 35. Existence of halodialkoxyalkanes. Simple synthesis of dialkoxymethanephosphonates, Chem. Ber, 101, 1250, 1968. 

Alkenes, R2C = CR2, can react with chlorine and water to form halohydrins, R2C(OH)C(Cl)R2. With alcohol (R OH) solvents, the product is a haloether, R2C(0R )C(C1)R2. In the presence of a carboxylic acid (R C02H), the products include the corresponding halohydrin esters, R2C(02CR ) CCIR2 (Wagner and Zook, 1965b). 

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