Synthesis of Alcohols by Nucleophilic Substitution

INDUSTRIAL SOURCES OF ALCOHOLS CARBON MONOXIDE AND ETHENE 

Let us now turn to the preparation of alcohols. We start in this section with methods of special importance in industry. Subsequent sections address procedures that are used more generally in the synthetic laboratory to introduce the hydroxy functional group into a wide range of organic molecules. 

Methanol is made on a multibillion-pound scale from a pressurized mixture of CO and H2 called synthesis gas. The reaction involves a catalyst consisting of copper, zinc oxide, and chromium(III) oxide. 

Changing the catalyst to rhodium or ruthenium leads to 1,2-ethanediol (ethylene glycol), an important industrial chemical that is the principal component of automobile antifreeze. 

Other reactions that would permit the selective formation of a given alcohol from synthesis gas are the focus of much current research, because synthesis gas is readily available by the gasification of coal or other biomass in the presence of water, or by the partial oxidation of methane. 

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The catalyst is phosphoric acid. The laboratory synthesis of alcohols is by nucleophilic substitution of haloalkanes. 

Z- and 4-alkoxyquinazolines are readily prepared by nucleophilic substitution reactions, and 2,4-dialkoxyquinazolines can simply be prepared by boiling 2,4-dichloroquinazolines with 2 equiv of an alkoxide in the appropriate alcohol solvent <1996HC(55)1>. The first substitution is in the more reactive 4-position, so it is possible to isolate both 4-alkoxy and 4-phenoxy monosubstitution products <1977EJM325, 2005BMC3681>, and this selectivity has been used to attach both 2,4,6- and 2,4,7-trichloroquinazoline to a solid support, via the 4-position, for subsequent solid-phase synthesis of 2,6- and 2,7-diamino-4(377)-quinazolinones <2003TL7533>. 

In a recent report, Shi et al. developed a valuable tool for the synthesis of 2,6-trans substituted morpholines by addition of water and alcohol to epoxy alkynes [109]. The procedure involved a domino three-membered ring opening, 6-exo-cycloisomerization, and subsequent intra-or intermolecular nucleophilic addition or a double-bond sequence. 

Carboxylates are stable to anhydrous hydrogen fluoride,30 but as described above, how ever, hemiacetal esters are readily cleaved and fluorinated by anhydrous hydrogen fluoride or 70% hydrogen fluoride/pyridine, this method has been widely applied in the synthesis of glycosyl fluorides from glycosyl esters for reviews see refs 29, 34, 277-279. 288, 289. Furthermore, p-toluene- or methanesulfonates (but not trifluoroacetates) of primary alcohols arc fluorinated by nucleophilic substitution using tctrabutylammonium hydrogen fluoride. This procedure is less suitable for secondary alcohols because of the considerable number of elimination products 306 for example, formation of 1 compared to 2.306... 

Variously substituted 2-azido-pyridines have been irradiated on a preparative scale in the presence of alcohols or amines for the synthesis of the corresponding variously substituted 1,3-diazepines, in good to high yields. In the presence of halo substituents on the pyridinium moiety, a nucleophilic substitution by the ZH reagent can also occur [93]. Among others, representative examples of obtained target are reported in Figure 12.1 [91, 93]. 

In the simplest of these, jS-enaminones are synthesized (equation 129) by the addition of amines to 1,3-diketones or /3-ketoesters. The reaction has been apphed to the Friedlander synthesis of quinolines by condensation of the enaminone and other carbonyl present in the substrate. Substituted pyrroles in equation (130) can be obtained as well when a propargyl group is present, by addition of the enaminone to the triple bond. Alcohols, thiols, and secondary phosphines have been also tested as nucleophiles with good results. A particularly interesting case is found in the condensation of indoles with 1,3-diketones to give substituted indol derivatives in equation (131). ... 

The Williamson synthesis involves nucleophilic substitution of alkoxide ion or phenoxide ion for halide ion it is strictly analogous to the preparation of alcohols by treatment of alkyl halides with aqueous hydroxide (Sec. 15.7). Aryl halides cannot in general be used, because of their low reactivity toward nucleophilic substitution. 

Nucleophilic substitution reactions have been effectively exploited in the synthesis of several classes of polymers. However, only scanty reports are available on the application of such reactions to the displacement of chlorine in bisdichloromaleimides, although several examples of displacement of chloride by nucleophiles in N-substituted dichloromaleimides exist in literature. Amines (5), phenols (6), and alcohols and thiols (7) have been used as nucleophiles in such reactions. 

Williamson s synthesis A method for the preparation of mixed ethers by nucleophilic substitution. A haloalkane is refluxed with an alcoholic solution of sodium alkoxide (from sodium dissolved in alcohol) ... 

Azides are useful intermediates for synthesis of various nitrogen-containing compounds. They undergo cycloaddition reactions, as will be discussed in Section 6.2, and can also be easily reduced to primary amines. Azido groups are usually introduced into aliphatic compounds by nucleophilic substitution. The most reliable procedures involve heating the appropriate halide with sodium azide in DMSO or DMF. Alkyl azides can also be prepared by reaction in high-boiling alcohols ... 

The ability of nucleophilic substitution to provide either 2,6-cis or 2,6-trans THP has been exploited in the synthesis of several natural products. Williams and coworkers reported the formation of both the A and B ring of leucascandrolide A by nucleophilic substitution (Scheme 14) [35]. Both examples relied oti a methanesulfonate leaving group and secondary alcohol nucleophile. Subjecting mesylate 44 (or 46) to sodium hydride deprotonation followed by heating resulted in THP product 45 (or 47) in 75 % yield as a single diastereomer. 

Activation of an allylic alcohol by metal catalysts can be used to facilitate addition of a variety of nucleophiles. This method has recently been adapted for the synthesis of spiroacetals via hemiacetals substituted with an allylic alcohol side chain (Scheme 17). 

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