Prin Cyclization Reaction

1.3. An Overview for the Synthesis of Tetrahydropyrans, Piperidines and Dihydro-γ-pyrone Derivatives

To build this class of heterocycles, many strategies have been developed over the years. The most widely used methods are the Prins cyclization, hetero-Diels–Alder (HDA) cyclization, oxonium-ene cyclization, the intramolecular Michael additions and ring-closing metathesis. Other strategies include electrophile-induced cyclizations of non-activated alkenes and Lewis acid promoted cyclizations of epoxy alcohols/amines. Reported methods used for six membered oxygen and nitrogen ring synthesis have their own advantages and disadvantages. Therefore, development of new and efficient methods is imperative especially to address the issue of diastereoselectivity. Among these methods stated, this thesis mainly discusses Prins, aza-Prins cyclization and HDA reactions in detail for the construction of six membered O- and N- heterocycles.

1.3.1. Prins Cyclization Reaction

In 1919 a Dutch chemist H. J. Prins has first reported

In detail, the Prins cyclization of homoallylic amines takes place in a fashion similar to that of homoallylic alcohols, whereby the non bonding electrons on the nitrogen initiate the sequence of reaction steps by attacking the electrophilic site of the aldehyde activated by an acid catalyst. The key intermediate of the aza-Prins cyclization is an iminium ion, in analogy to the oxonium ion. Compared to classical Prins cyclization, examples of aza-Prins cyclization using iminium ions leading to nitrogen-containing heterocycles have been less developed in the literature due to less electrophilic nature of iminium ions compared to oxo-carbenium ions. Whereas, aza-Prins cyclization of acyclic/cyclic N-acyliminium ion intermediates to achieve piperidine ring containing mono and bicyclic compounds is well explored due to more electrophilic nature of N-acyliminium