Isocyanides have been important building blocks in organic synthesis since the discovery of the Ugi reaction and related isocyanide-based multicomponent reactions. In the past decade isocyanides have found a new application as versatile C1 building blocks in palladium catalysis. Palladium-catalyzed reactions involving isocyanide insertion offer a vast potential for the synthesis of nitrogen-containing fine chemicals. This Minireview discusses all the achievements in this emerging field.

O(2) in, H(2)O out: Various diamines and related bisnucleophiles readily undergo oxidative isocyanide insertion with Pd(OAc)(2) (1 mol %) as the catalyst and O(2) as the terminal oxidant to give a diverse array of medicinally relevant N heterocycles. The utility of this highly sustainable method is demonstrated by a formal synthesis of the antihistamines astemizole and norastemizole.

The importance of palladium‐catalyzed cross coupling reactions in contemporary organic synthesis is undisputed and underlined by the Nobel Prize for Chemistry in 2010. In addition to the highly efficient cross coupling reactions for single CC bond construction, palladium‐catalyzed cascade processes involving multiple bond formations have emerged in recent years as valuable tools for the rapid synthesis of complex molecular scaffolds. This review presents an overview of the most relevant developments in this field, with a focus on the generation of diverse poly‐ and heterocyclic scaffolds. The generally well understood reactivity of palladium has allowed the discovery of many intriguing novel cascade processes, and the creativity of the synthetic community will undoubtedly lead to many more discoveries in the future.

Isocyanides have emerged as valuable C1 building blocks in palladium catalysis. Their potential has, however, mainly been exploited for the synthesis of amidines and amidine-containing heterocycles. To illustrate the broader applicability of isocyanides, we have recently developed a novel oxidative coupling of diamines and isocyanides furnishing valuable guanidine-containing heterocycles. We here report the extension of this protocol to the coupling of anthranilic acids and isocyanides leading to medicinally relevant 2-aminobenzoxazinones. This is a particularly challenging substrate class for this reaction due to the possibility of undesired decarboxylative pathways and the susceptibility of the products to nucleophilic attack. Therefore, this work underlines the generality and broad potential of the oxidative coupling of bisnucleophiles and isocyanides, facilitating the further implementation of this chemistry in library design.

A new synthetic approach to 4-aminopyrido-[2,3-d]pyrimidines and 4-aminopyrido [3,2-d]pyrimidines based on palladium-catalyzed reaction of isocyanides with readily available N-(bromopyridyl)amidines is reported. The target heterocycles were obtained in generally good to excellent yield. For the two regioisomeric pyrimidopyrimidines, we compared our approach involving oxidative addition with the analogous C−H activation protocol because both methods have been reported for the synthesis of 4-aminoquinazolines. We found that the C−H activation protocol does not allow one to obtain the target pyridopyrimidines, but the imidoylative cross-coupling protocol provided a new entry to the synthesis of these medicinally important scaffolds.