Anisole ortho substitution

Only one example, showing high stereoselectivity, is known in this class of reactions. On treatment of the acyclic glycine cation equivalent 1 (see Appendix), containing the ( + )-cam-phor-10-sulfonamide ester as a chiral auxiliary, with boron trifluoridc and anisole at 0"C a mixture of aromatic substitution products is obtained in essentially quantitative yield 55. Besides 11 % of cuV/io-substitution product, the mixture contains (R,S)-2 and its (/ ,/ )-epimer in a ratio >96 4 (NMR). The same stereoisomer 2 predominates when the reaction is conducted in sulfuric acid/acetic acid 1 9, although the selectivity is slightly lower (91 9 besides 25% of ortho substitution). 

Scheme 11.11 gives some representative preparative reactions based on these methods. Entry 1 is an example of the classical procedure. Entry 2 uses crown-ether catalysis. These reactions were conducted in the aromatic reactant as the solvent. In the study cited for Entry 2, it was found that substituted aromatic reactants such as toluene, anisole, and benzonitrile tended to give more ortho substitution product than expected on a statistical basis.180 The nature of this directive effect does not seem to have been studied extensively. Entries 3 and 4 involve in situ decomposition of A-nitrosoamides. Entry 5 is a case of in situ nitrosation. 

Phenol derivatives have also been oxidized anisole undergoes substitution both in the ortho (30%) and the para position (70%) (Romano et al, 1990). 

In the case of anisole, the reaction takes following route shown in Scheme 4-10. The reaction yields only products of the ortho and para substitutions the meta isomer is lacking. If it were a standard radical substitution, the meta isomer would obviously be formed in a certain amount (i.e., in the same amount as that for ortho-substituted product). 

With arenes bearing a single resonance donor substituent (NR2, OMe, F), the addition is strongly preferred at the meta position, with small amounts of ortho substitution (0-10%). " The meta acylation of anisole, using a carbonyl anion equivalent as the nucleophile, illustrates the unique regioselectivity available with the Cr(CO)3 activation (equation 115). ... 

On the other hand, the reaction with anisol or dimethyl aniline afford the product 33) or 34), indicating that the reaction takes place on the phenyl carbon. The striking fact is that only the ortho-substituted compound is obtained (regio-specific reaction) (Eqs. (19) and (20)). 

Selectivity is more complicated with a methyl or chloro substituent. Again, meta substitution is always significant, but ortho substitution can account for 50-70% of the mixture in some cases [2]. More reactive anions (1,3-dithianyl) and less substituted carbanions (e.g., tert-butyl lithioacetate) tend to favor ortho substitution. Representative examples are shown in Table 3. Entries 2-4 show that variation of reaction temperatures from -100 °C to 0 °C has no significant effect in that highly selective system. The added activating effect of the Cl substituent allows addition of the pinacolone enolate anion (entry 11), whereas no addition to the anisole nor toluene ligand is observed with the same anion. 

Because the intermediate formed in para (or ortho) substitution of anisole is more stable than that formed in meta substitution of anisole or in substitution of benzene, the transition state leading to the para (or ortho) intermediate is more stable than the transition states for meta substitution of anisole or substitution of benzene itself... 

As a result, we can expect para (or ortho) substitution to occur more rapidly than the other two reactions (Fig. 14.67). In fact, the chlorination of anisole gives only... 

The Ciba-Geigy researchers, attempting cleavage of the 2-cephem benz-hydryl esters (213) with trifluoroacetic acid in the presence of anisole, found that, besides an ester cleavage, a mixture of para- and ortho-substituted anisyl derivatives (214 and 215) was obtained. Similarly, the use of other types of aromatic C-nucleophiles (i.e., phenol, thiophene) in the same type of reactions gave compounds of similar structure (216). 

It has been shown that it is possible to compel regiospecific para substitution by enclosing the substrate molecules in a cavity from which only the para position projects. Anisole was chlorinated in solutions containing a cyclodextrin, a molecule in which the anisole is almost entirely enclosed (see Fig. 3.4). With a high enough concentration of cyclodextrin, it was possible to achieve a para/ortho ratio of 21.6 (in the absence of the cyclodextrin the ratio was only 1.48). This behavior is a model for the regioselectivity found in the action of enzymes. 

Anisole has charge densities as shown in (85) and (86). This indicates that ground state anisole should undergo electrophilic substitution at the ortho... 

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