Reductive etherifications

ANILINES, BENZYL AMINES, AND ANALOGUES An orally active local anesthetic agent that can be used as an (intiarrhythmic agent is meobenti ne (57). Its patented synthesis starts with -hydroxyphenyl nitrile and proceeds by dimethyl sulfate etherification and Raney nickel reduction to Alkylation of -methyl-dimethylthiourea with completes l.he synthesis of meobenti ne (57). ... 

Oriyama and coworkers reported an iron-catalyzed reductive etherification of carbonyl compounds with triethylsilane and alkoxytriaUcylsilane [149, 150] and alcohols (Scheme 48) [151]. 

Scheme 48 Iron-catalyzed reductive etherification of carbonyl compounds...

Although some methods for reductive etherifications of carbonyl compounds have been reported [152-162], the iron-catalyzed version possesses several advantages (1) fairly short reaction times are needed, (2) not only trimethylsilyl ether but also triethylsilyl and butyldimethylsilyl ethers and alcohols are adaptable, and (3) a broad substrate scope. 

Ye et al. reported that the reduction of 2,4-dichlorophenyl-2-chloroethanone 1 with potassium borohydride in dimethylformamide to give 90% a-chloromethyl-2,4-dichlorobenzyl alcohol 2. Alkylation of imidazole with compound 2 in dimethyl formamide in the presence of sodium hydroxide and triethylbenzyl ammonium chloride, gave l-(2,4-dichlorophenyl-2-imidazolyl)ethanol 3 and etherification of 3 with 2,4-dichlorobenzyl chloride under the same condition, 62% yield of miconazole [9]. 

The manufacture of fine chemicals and pharmaceuticals generates in the order of 25-100 times more waste than product [52], Inorganic salts account for the bulk of the waste and are most often produced by neutralization of acidic or basic solutions [53]. Salts can pollute soil and ground water, lower the pH of atmospheric moisture and they may contribute to acid dew or acid rain [6]. For cleaner production, their minimization is essential and hence our concentration on new processes, such as the etherification (discussed in Sect. 2.6.3.1) and hydrogen transfer reduction (Sect. 2.6.3.2), that avoid salt formation and the use of salts. 

Reductive Etherification. As indicated earlier, aldehydes as well as ketones often give very good yields of ethers when they are treated with Br0nsted acids or other electrophilic species in the presence of organosilicon hydrides (Eq. 172). In the absence of added alcohols, symmetrical ethers are obtained. 

Cyclic ethers can also be formed in a fashion similar to that of the reactions described previously (Eq. 186),306,342 and also result from the reductive etherification of bis(trimethylsilylated) diols and dialdehydes (Eq. 187).343... 

Electrogenerated acid (EG acid), aldehyde to alcohol reduction, etherification, 65-69... 

Tetrahydropyran (THP), aldehyde etherification, 67-68 Tetralin compounds, 5-methoxytetralin reduction of substituted naphthalene, 132-133... 

Like alkynes, a variety of mechanistic motifs are available for the transition metal-mediated etherification of alkenes. These reactions are typically initiated by the attack of an oxygen nucleophile onto an 72-metalloalkene that leads to the formation of a metal species. As described in the preceding section, the G-O bond formation event can be accompanied by a wide range of termination processes, such as fl-H elimination, carbonylation, insertion into another 7r-bond, protonolysis, or reductive elimination, thus giving rise to various ether linkages. 

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