Electrophilic aromatic synthesis strategies

It is particularly difficult to carry out a ring opening in compounds containing the oxabicyclo[2.2.1] nucleus without concomitant aromatization, because the strong acidic conditions can also lead to dehydration. On the other hand, inducing aromatization under controlled conditions permits the synthesis of highly-substituted aryl compounds as an alternative synthetic strategy to traditional electrophilic aromatic substitution . The methods to aromatize oxabicyclo [2.2.1 ] heptanyl derivatives by the use of acids and low valent metals have been reviewed [172]. 

The fact that benzene derivatives are much more generally accessible than pyrroles has relegated pyrrole annelation to a relatively minor role in indole synthesis. Nevertheless the concept provides a viable synthetic approach and the existing methods serve as useful prototypes. One strategy is to build up an appropriately functionalized side-chain and complete indole formation by electrophilic substitution-aromatization. Reactions (135)-(137) illustrate this type of approach (79TL3477, 79JA257, 73JPR295). 

The first strategy you should try out when faced with the synthesis of an aromatic heterocyclic ring is the disconnection of bonds between the heteroatom or atoms and carbon, with the idea of using the heteroatoms as nucleophiles and the carbon fragment as a double electrophile. 

The substitution of pure benzene by an electrophile will result in the formation of a monosubstituted product, which is capable of undergoing further substitution reactions. When designing the strategy for the synthesis of an aromatic compound, there are two principal points that must be borne in mind, namely first, the reactivity of the monosubstituted product compared with that of the original benzene and second, the position on the aromatic ring where the second substitution reaction will take place. These two issues will now be examined, and it will be seen that they are, at least to some extent, dependent upon each other. 

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