Benzylic leaving groups

The first of the few low-temperature methods for the formation of an o-QM was a method developed by Rokita.5 It is principally used for reversible DNA alkylation. However, it has recently begun to find its way into some synthetic applications. It utilizes a silylated phenol, which proves vastly more manageable as an o-QM precursor than the corresponding o-hydroxyl benzyl halide (Fig. 4.6). In this kinetically controlled process, expulsion of a benzylic leaving group is triggered at low temperature by treatment with a fluoride ion, which causes a (3-elimination. 

Arg217 located in the S4-S5 subsites but this did not occur. The electron-donating methoxy substituent was introduced to enhance the departure of the benzylic leaving group X. But there was no enhancement.35... 

For a given set of substituents at position C3, the efficiency of the inhibition depends on the nature of the benzylic leaving group X (Table 11.4). No significant inactivation is found with a fluorine atom at this position. The brominated azetidinone (24b) is a better inactivator than its chlorinated counterpart (24a). 

If the arenes are very electron-deficient direct attack of the nucleophile at the arene might also compete with displacement of the benzylic leaving group, to yield complex structures such as that shown in Scheme 4.28. 2-Nitrobenzyl halides can also react with amines to yield, instead of simple products of nucleophilic substitution, 2fi-indazoles [122] (Scheme4.28). 4-Nitrobenzyl halides, however, yield the expected benzyl amines on treatment with amines [123]. 

To complete the synthesis of the photo-switch conqxinent of the channel, Williamson etiier syrithesis using the primary alkoxide as the nucleophile and a suitable benzylic leaving group O r, OTs) as die electrophile will be required. Our synthetic progress towards the final target will be reported subsequently. 

The first path is expected to be inefficient, because it will be difficult to achieve monoaUcylation. More likely, polyaUcylation will occur, especially with the activated benzylic leaving group. The second path is expected to be more efficient, which gives the following synthesis ... 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

The most common leaving groups are sulfonate esters and halides. For the sake of convenience, the discussion of certain dehalogenation reactions is also included in this section even though they may not involve 8 2 type displacement. Benzylic alcohols are also known to be displaced by hydrides or deuterides, but there is no evidence for the application of these reactions to the steroid field. 

The reaction works well with primary alkyl halides, especially with allylic and benzylic halides, as well as other alkyl derivatives with good leaving groups. Secondary alkyl halides give poor yields. Tertiary alkyl halides react under the usual reaction conditions by elimination of HX only. Nitriles from tertiary alkyl halides can however be obtained by reaction with trimethylsilyl cyanide 4 ... 

The Cannizzaro reaction takes place by nucleophilic addition of OH- to an aldehyde to give a tetrahedral intermediate, which expels hydride ion as a leaving group and is thereby oxidized. A second aldehyde molecule accepts the hydride ion in another nucleophilic addition step and is thereby reduced. Benzaldehyde, for instance, yields benzyl alcohol plus benzoic acid when heated with aqueous NaOH. 

Alkylation reactions are subject to the same constraints that affect all Sn2 reactions (Section 11.3). Thus, the leaving group X in the alkylating agent R—X can be chloride, bromide, iodide, or tosylate. The alkyl group R should be primary or methyl, and preferably should be allylic or benzylic. Secondary halides react poorly, and tertiary halides don t react at all because a competing E2 elimination of HX occurs instead. Vinylic and aryl halides are also unreactive because backside approach is sterically prevented. 

This conversion has been used as a key step in the preparation of optically active aziridines from optically active 1,2-diols (prepared by 15-46). ° Even hydrogen can be the leaving group. Benzylic hydrogens have been replaced by N3 by treatment with HN3 in CHCI3 in the presence of DDQ (p. 1511). °°... 

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