Preparation of Alcohols, Ethers, and Epoxides

Alcohols and ethers are both common products of nucleophilic substitution. They are synthesized from alkyl halides by Sn2 reactions using strong nucleophiles. As in all Sn2 reactions, highest yields of products are obtained with unhindered methyl and 1 ° alkyl halides. 

The preparation of ethers by this method is called the Williamson ether synthesis, and, although it was first reported in the 1800s, it is still the most general method to prepare an ether. Unsymmetrical ethers can be synthesized in two different ways, but often one path is preferred. 

For example, isopropyl methyl ether can be prepared from CH3O and 2-bromopropane (Path [a]), or from (CH3)2CHO and bromomethane (Path [b]). Because the mechanism is 8 2, the preferred path uses the less sterically hindered halide, CH3Br—Path [b]. 

Probl6m 9.11 Draw the organic product of each reaction and classify the product as an alcohol, symmetrical ether, 

Draw two different routes to each ether and state which route, if any, is preferred. 

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It does not homopolymerize easily and hence can be stored as a liquid. It undergoes many addition reactions typical of an olefin. Reactions inclnde preparation of linear dimers and trimers and cyclic dimers (21,22) decomposition at 600°C with subsequent formation of octafluoro-2-butene and octafluoroisobutylene (23) oxidation with formation of an epoxide (24), an intermediate for a number of perflu-oroalkyl perfluorovinyl ethers (25,26) and homopolymerization to low molecular weight liquids (27,28) and high molecular weight solids (29,30). Hexafluoropropylene reacts with hydrogen (31), alcohols (32), ammonia (33), and the halogens and their acids, except I2 and HI (31,34-36). It is used as a comonomer to produce elastomers and other copolymers (37-41). The toxicological properties are discussed in Reference 42. 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

Benzyloxy-2-methylpropane-l,2-diol, a desymmetrized form of 2-methylpropane-1,2,3-triol with its terminal hydroxy being protected as a benzyl ether, was prepared using the B. subtilis epoxide hydrolase-catalyzed enantioselective hydrolysis of the racemic benzyloxymethyl-l-methyloxirane readily available from methallyl chloride and benzyl alcohol. The preparation of the racemic epoxide, a key intermediate, was described in Procedures 1 and 2 (Sections 5.6.1 and 5.6.2), its overall yield being 78 %. The combined yield of enantiomerically pure (7 )-3-benzyloxy-2-methylpropane-l,2-diol was 74 % from ( )-benzyloxymethyl-l-methyloxirane, as described in Procedures 3-5 (Sections 5.6.3 and 5.6.5), with the overall procedures leading to the biocatalytic dihydroxylation of benzyl methallyl ether . 

Since the starting tellurides are easily prepared (see Section 3.1.3.2) from the corresponding alkyl bromides and tellurolate ions, and -hydroxyalkyl tellurides by the opening of epoxides with the same reagents, the combined procedures furnish a method for the dehydrobromination of alkyl bromides and for the conversion of epoxides into allylic alcohols. Moreover, combining the telluroxide elimination with the methoxytelluration of olefins (see Sections 3.9.3.2 and 4.4.8.3), allylic and vinylic ethers are easily prepared. 

Many other uses of a-sulfinyl carbanions are found in the literature, and in the recent past the trend has been to take advantage of the chirality of the sulfoxide group in asymmetric synthesis. Various ways of preparation of enantiopure sulfoxides have been devised (see Section 2.6.2) the carbanions derived from these compounds were added to carbonyl compounds, nitriles, imines or Michael acceptors to yield, ultimately, with high e.e. values, optically active alcohols, amines, ethers, epoxides, lactones, after elimination at an appropriate stage of the sulfoxide group. Such an elimination could be achieved by pyrolysis, Raney nickel or nickel boride desulfurization, reduction, or displacement of the C-S bond, as in the lactone synthesis reported by Casey [388]. 

In a short known reaction sequence, enal 250 was obtained from commercially available material 184). With methylamine and magnesium sulfate imine 251 was formed and combined with acyl chloride 252 185) (>4 steps). The use of low temperatures for this acylation led exclusively to the less substituted dienamide 253. The desired basic skeleton of dendrobine 254 was obtained by cyclizing 253 at 180°C in an acceptable 50% yield, Adduct 254 was accompanied by small amounts of the exo-adduct. Epoxidation led exclusively to exo-epoxide 255, which by means of trimethylsilyltriflate was converted into the allylic silyl ether. Acid treatment liberated the hydroxy group and subsequent oxidation of alcohol 256 led to enone 163, an intermediate of Inubushi s dendrobine synthesis and thus concluded this formal synthesis. The intermediate 163 was obtained from commercially not available materials in seven steps in 22.5% overall yield. To reach ( )-dendrobine according to Inubushi et al. would afford six additional steps, reducing the overall yield to 0.4% without including the preparation of the starting materials from commercially available compounds. 

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