Multiple Isocyanide insertions promoted by protic and Lewis acids

The protonation, or Lewis Acid complexation, of electrophiles can trigger the sequential insertion of two or more isocyanides resulting in valuable iminonitriles or heterocycles. The number of insertions is controlled by the nature of the alkyl- or arylisocyanide and by the presence of a proximal nucleophile capable of attacking the intermediate nitrilium; loss of an alkyl group from the nitrilium or attack by a nucleophile terminates further isocyanide insertions. The mechanistic survey of protic and Lewis acid-promoted isocyanide insertions aims to provide a fundamental understanding of the reactivity and selectivity to facilitate synthetic applications. The review is structured with an introductory overview followed by a mechanistic analysis before moving to a survey of double insertions, which are the most prevalent, then triple insertions; the survey concludes with the sole example of a quadruple insertion. The hope is that the insight contained in the review will aid in applying protic and Lewis acid-activated isocyanide insertions to prepare an array of complex heterocycles.