Higher-order multicomponent reactions: beyond four reactants.

Multicomponent reactions (MCRs) are by far the most successful class of reactions leading to high structural diversity and molecular complexity through a single transformation. As part of the ongoing search for pharmacologically active lead structures, the obtained structural diversity allows for the fast exploration of a large chemical space. Not surprisingly, the development of MCRs, leading to new structural frameworks or serving as key transformations in the total synthesis of natural products, has expanded rapidly over the last few decades. To date a multitude of new three- and four-component reactions have already been described; however, examples of "higher-order" MCRs where five or even more components are combined in a single reaction vessel are remarkably scarce. This tutorial review aims to critically describe the developments achieved in recent years, charting the ideas, challenges, and milestone reactions that were essential for the progress of this field.