Nonsymmetrical Bis-Azine Biaryls from Chloroazines: A Strategy Using Phosphorus Ligand-Coupling.

Distinct approaches to synthesize bis-azine biaryls are in demand as these compounds have multiple applications in the chemical sciences and are challenging targets for metal-catalyzed cross-coupling reactions. Most approaches focus on developing new reagents as the formal nucleophilic coupling partner that can function in metal-catalyzed processes. We present an alternative approach using pyridine and diazine phosphines as nucleophilic partners and chloroazines where the heterobiaryl bond is formed via a tandem SAr-phosphorus ligand-coupling sequence.

Heterobiaryl synthesis by contractive C-C coupling via P(V) intermediates.

Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C-C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C-H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond.

A Strategy to Aminate Pyridines, Diazines, and Pharmaceuticals via Heterocyclic Phosphonium Salts.

A straightforward process to aminate pyridines and diazines is presented by reacting phosphonium salt derivatives with sodium azide. The iminophosphorane products are versatile precursors to several nitrogen-containing functional groups, and the process can be applied to building block heterocycles, to drug-like fragments, and for late-stage functionalization of complex pharmaceuticals. Appealing features of this strategy include using C-H bonds as precursors, precise regioselectivity, and a distinct scope from other amination methods, particularly those relying on halogenated azaarenes.

Selective Functionalization of Pyridines via Heterocyclic Phosphonium Salts.

Methods that directly functionalize pyridines are in high demand due to their presence in pharmaceuticals, agrochemicals, and materials. A reaction that selectively transforms the 4-position C-H bonds in pyridines into C-PPh groups that are subsequently converted into heteroaryl ethers is presented. The two step sequence is effective on complex pyridines, pharmaceutical molecules, and other classes of heterocycles.