Halides, alkyl, base induced reactions

Although aluminium alkoxides are able to promote base-induced reactions, the basic conditions involved are not extremely strong and many base-sensitive functional groups remain unaffected during Oppenauer oxidations, including alkyl halides,51 epoxides52 and most esters.53 On the other hand, the very sensitive formate esters are hydrolyzed under Oppenauer conditions and the resulting alcohols are oxidized in situ.25... 

As an example of their use in organic chemistry, the analgesic drug Pravadoline has been synthesized in two steps using 1-butyl-3-methylimidazolium hexafluorophosphate, abbreviated [bmimllPF J, as the solvent for both steps. The first step is a base-induced reaction of 2-methylindole with a primary alkyl halide, and the second is a F riedel-Crafts acylation. Both steps take place in 95% yield, and the ionic solvent is recovered simply by washing the reaction mixture, first with toluene and then wMth water. We ll be hearing a lot more about ionic solvents in coming years. 

In 1,2-eliminations involving carbon atoms (i.e. most), the atom from which Y is lost is usually designated as the l-(a-) carbon and that losing (usually) H as the 2-(/ -) carbon in the older a/J-terminology, the a- is commonly omitted, and the reactions are referred to as p-eliminations. Among the most familiar examples are base-induced elimination of hydrogen halide from alkyl halides—this almost certainly the most common elimination of all—particularly from bromides (1) ... 

The synthesis of stereodefined acyclic alkenes via 3-elimination reactions—such as (1) dehydration of alcohols, (2) base-induced eliminations of alkyl halides or sulfonates (tosyl or mesyl esters), and (3) Hofmann eliminations of quaternary ammonium salts—often suffers from a lack of regio- and stereoselectivity, producing mixtures of isomeric alkenes. 

Ethylene oxide or 1,2-epoxybutane may also be used for the synthesis of ylides. The resulting ylide is in equilibrium with its conjugated salt (equation 15). The use of ethylene oxide offers some advantages over more conventional bases used in Wittig reactions. The application is simple since ylides and most often also phosphonium salts (from phosphine and alkyl halide) need not to be prepared separately. The reaction medium is neutral, so that base-induced side reactions fail to appear. The method is however less applicable to weakly acid phosphonium salts, since deprotonation requires high temperatures (150 C). 

In a so-called vicarious nucleophilic substitution of hydrogen,75 2,3-diphenylpyrido[2,3-6]-pyrazine is alkylated in the 8-position by [(chloromethyl)sulfonyl]benzene. This reaction proceeds by addition of the carbanion to the electron-deficient ring position of a nitroarene or electrophilic heteroaromatic system, followed by base-induced -elimination of the corresponding hydrogen halide.76,77 As with quinoxalines and naphthyridines, the reaction with pyrido[2,3-6]pyrazines also affords products bisannulated at the pyrazine or the pyridine moiety, depending on the kind of 2/3-substitution (cf. Section 7.2.3.1.2.2.2.). 

The preparation of indoles by the benzyne route is illustrated by the base-induced cyclization of the amino-alcohols (171 R = H or Me) to indole and 3-methylin-dole, respectively/ The photochemical reaction of o-bromo- or o-iodo-aniline with the enolates (172 R = H, Me, or PrO leads to indoles (173)/ The salt (174), generated by the action of lithium di-isopropylamide on o-tolyl isocyanide, serves as a source of diverse indole derivatives (i) it cyclizes spontaneously to 1-lithioindole, which forms 3-alkyl-indoles on treatment with alkyl halides in the presence of magnesium iodide, (ii) it reacts with allyl esters RC02CH2CH=CH2 (R = alkyl or aryl) to give the ketones (175), which cyclize... 

One of the most commoidy used methods for forming carbon-carbon double bonds is by -elimination reactions of the types shown in Scheme 2.1, where X = e.g. OH, OCOR, halogen, OSO2R, NRa, etc. Included among these reactions are acid-catalysed dehydrations of alcohols, solvolytic and base-induced eliminations from alkyl halides or sulfonates and the Hofmann elimination from quaternary ammonium salts. They proceed by both E2 (elimination bimolecular) and E1 (elimination... 

The Julia olefination allows the generation of a double bond by alkylation of a suUbne, followed by a base-induced elimination of ben-zenesulfinic add. The water-soluble sulfinate can be separated off, and recovered as the free sulfinic add. The sulfone is then obtained by reaction ofthe sulfinic acid with the appropriate alkyl halide. [73]... 

Because of the harsh conditions and high basicity of fluoride anions, these reactions are often accompanied by base-induced y3-elimination and decomposition of the TAA catalyst via the Hoffmann-type degradation. Particularly, secondary alkyl halides, cyclohexyl chloride, and 2-octyl bromide, in the reaction with KF under these conditions undergo -elimination. 

For efficient action of Y as cocatalysts, it is necessary that in reactions with alkyl halides they behave as bases abstracting proton not as nucleophiles entering undesired nucleophilic substitution. From a variety of possible Y-H, only OH acids—alcohols and phenols, and to smaller extent some NH acids—are shown to be proper cocatalysts. In a model studies of base-induced PTC j8-elimination of HBr from cyclohexyl bromide, it was shown that benzyl and benzhydryl alcohols, 2,2,2-trifluoroethanol, trifluoromethylphenyl carbinol, and mesitol are particularly efficient cocatalysts (71) as shown in equation 159. 

Purpose. This reaction illustrates the base-induced dehydrohalogenation of alkyl halides with strong base and is used extensively for the preparation of alkenes. The stereo- and regiochemical effects of the size of the base is investigated, and the product mixture is analyzed by the use of gas chromatography. 

Geometrical Considerations in the E2 Elimination Reaction. Base-induced elimination of alkyl halides (dehydrohalogenation) is a general reaction and is an excellent method for preparing alkenes.This process is often referred to as -elimination, since a hydrogen atom is always removed p to the halide (leaving group) ... 

There are also a series of more complex eliminations that you should be aware of (Eqs. 10.63-10.67), although we are not going to look at these in any detail. One is the elimination of 1,2-dihaloalkanes and 1,4-dihaloalkanes (the Grob fragmentation) using Zn to create al-kenes or dienes (Eqs. 10.63 and 10.64, respectively). The first step in both reactions involves the oxidative addition of Zn to a C-X bond, a reaction we will cover in detail in Chapter 12. Other eliminations involve y-amino alkyl halides, which can spontaneously undergo elimination (Eq. 10.65), and the base-induced eliminations of both (3-hydroxyketones (Eq. 10.66, the reverse aldol reaction) and 8-ketoketones (Eq. 10.67, the reverse Michael addition). 

The reaction of an alkyl halide or tosylate with a nucleophile/base results either in substitution or in elimination. The resultant nucleophilic substitution and base-induced elimination reactions are two of the most widely occurring and versatile reaction types in organic chemistry, both in the laboratory and in biological pathways. 

Here too, a second alkylation can be made to take place yielding RC=CR or R C=CR. It should, however, be remembered that the above carbanions—particularly the acetylide anion (57)—are the anions of very weak acids, and are thus themselves strong bases, as well as powerful nucleophiles. They can thus induce elimination (p. 260) as well as displacement, and reaction with tertiary halides is often found to result in alkene formation to the exclusion of alkylation. 

---