Haloethers synthesis

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). 

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>. 

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

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

The nonoxidative applications of thallium in organic synthesis are relatively few. Organothallium reagents act as mild nucleophiles. Thus, acid chlorides can be alkylated by R3TI, as can a-haloethers. Nucleophilicity is greater for R4TD. Alkyltrimethylthallate(III) is prepared from MesTl and RLi, and may be used to alkylate a,/ -unsaturated ketones. ... 

Although secondary alkyl halides are generally unsatisfactory in the phase transfer catalyzed Williamson ether synthesis, the more reactive a-haloethers are as useful as, and more reactive than, simple alkyl halides. Thus the Koenigs-Knorr reaction has been successfully executed under phase transfer conditions [10]. a-2-Bromo-3,4,5,6-... 

Haloetherification (Table 43.6) Considering the abundance of bioactive haloethers in nature, one may assume that the catalytic enantioselective haloetherification of alkenyl alcohols would be a desirable tool to secure such natural products. Although the practical application of this method to the total synthesis of halogenated ethers remains unexplored, it is relevant to briefly mention recent progress in this area. 

Analogously, aryl 2-chloro[l- C]ethyl carbinols 49 (Figure 11.19) are accessible by CBS- or IpCaBCl-mediated reduction of aryl (2-chloro)ethyl[carbonyl- C]ketones e.e.s are usually > 90%. Replacement of chlorine with iodine followed by treatment with a primary amine converted haloalcohol 49 (Ar = thien-2-yl) into the 3-aryl-3-hydroxy[3- C]propy-lamine derivative 52, which served as the penultimate intermediate in the preparation of the carbon- 14-labeled CNS-active drug duloxetine" . Furthermore, Mitsunobu reaction (DEAD or ADDP, PhsP or BU3P) on 49 (Ar = phenyl) in the presence of various phenols provided the respective (R)- j8-haloethers with inversion of the configuration at the stereogenic center. This route was followed for the synthesis of [ CJatomoxetine and one of its metabolites. ... 

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