Mechanisms of Sulfanyl (RS) Migrations: Synthesis of Heterocycles

Thiiranium (episulfonium) ions had been acknowledged as reaction intermediates for many years, but it was not until 1977 that Nicolaou demonstrated systematically that these reactive heterocyclic cations could be trapped by carboxylic acids to give lactones. In the years that followed this report, extensive research greatly extended the scope of this reaction, particularly with regard to the methods for generating thiiranium ions, the types of nucleophiles that are compatible with this reaction, and the selectivity involved in the cyclization reactions. For many years we have been using thiiranium ions for the synthesis of saturated heterocycles. Whereas Nicolaou's method relied on electrophilic sulfenylation of alkenes, we have generated thiiranium ions by displacement of a leaving group with neighboring‐group participation by a sulfanyl group. Many of the examples we have reported are of cyclizations that are reversible and so where two (and in some cases more) products can result, the outcome of the reactions provides fundamental information about the relative stability of different heterocyclic ring systems. This Review will begin with a brief introduction to sulfanyl participation as a method for generating thiiranium (and thiolanium) ions, and will go on to explore the idea of using sulfanyl migrations in synthesis. Initially, emphasis will be placed on mechanisms of [1,2] sulfanyl migrations: we will look specifically at [1,2] sulfanyl migrations (usually PhS) with elimination, substitution, and cyclization. Emphasis will then shift to the factors that affect the outcome of cyclization reactions. In particular, we will cover cyclizations with hydroxy nucleophiles and examine situations in which there are more than one hydroxy nucleophile present. We will also examine cyclizations with other nucleophiles, namely amines and sulfides. After our discussion of [1,2] sulfanyl migrations, we will look very briefly at the scope of [1,4] sulfanyl participation, before finally drawing up some guidelines that (we hope) will help other organic chemists take advantage of the rearrangement reactions that the sulfanyl group has to offer. Cyclization reactions involving thiiranium and thiolanium ion intermediates lead to highly substituted saturated O, N, and S heterocycles in high yield and with complete stereocontrol (see scheme).