Heterocycle-assisted syntheses

Just like a halogen atom or a diazonium group, several neutral or charged heterocyclic moieties can act as efficient leaving groups and therefore be considered as useful synthetic auxiliaries, provided:
  1. the starting heterocycle is cheap or readily available;
  2. the heterocyclic derivative can be prepared in high yield;
  3. the heterocyclic moiety can be readily displaced;
  4. the target molecule can be isolated in high yield and should be hardly obtained by another synthetic pathway;
  5. the heterocyclic moiety can be readily recyclable.



Numerous benzotriazole derivatives as well as pyridinium salts fulfill those requirements.

Benzotriazole is a weak acid (pKa ~ 8, like penta-2,4-dione); it readily reacts, i.a., with an aldehyde and an amine in a three-component synthesis to yield an aminal for which an equilibrium with corresponding charged species can be considered. Further reaction with a nucleophile is accompanied by the displacement of the benzotriazole anion and affords a highly substituted amine. As demonstrated by A.R. Katritzky et al., that is only one example of the numerous synthetic possibilities offered by the benzotriazole chemistry.



In 1987, E. Anders and J. Tropsch (Bull. Soc. Chim. Belges, 96, 719 – 720, 1987) described the first synthesis of N-(1-chloroalkyl)pyridinium chlorides from pyridine, aldehydes, and thionyl chloride. We have subsequently proven that such salts represent useful activated equivalents of the corresponding starting aldehydes. Let us emphasize, among the various examples we studied, that those pyridinium derivatives can be involved in the preparation of Hantzsch esters (N-unsubstituted as well as N-substituted) and in the direct synthesis of benzimidazoles, imidazopyridines, as well as perimidines, without the need for an external oxidant.


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