A general, convenient, and friendly route for preparing a versatile building block of isocyanides from primary amines is developed. Difluorocarbene, generated in situ from decarboxylation of chlorodifluoroacetate, reacts efficiently with primary amines to produce isocyanides. Various primary amines are well tolerated, including aryl, heteroaryl, benzyl, and alkyl amines, as well as amine residues in amino acids and peptides. Late-stage functionalization of biologically active amines is demonstrated, showing its practical capacity in drug design and peptide modification.

A one-pot three-component reaction of two anilines (or one aniline and one alkylamine) and in situ-generated difluorocarbene is developed herein to enable efficient construction of formamidines. Crucial formimidoyl fluoride intermediate RN� CHF is proposed from the reaction of a primary aniline and difluorocarbene. Ensuing nucleophilic iminyl substitution of this intermediate with a second amine allows cross-condensation of the two amines to produce formamidines. When only one type of primary aniline is used as the substrate, the difluoromethylated homo-condensation products can also be produced under a 1:1 molar ratio of aniline/difluorocarbene. Intramolecular variant of this method allows concise synthesis of benzimidazoquinazolines and nitrogen-fused/spirocyclic compounds, showing the potential of this method in organic synthesis. More interesting reactions are anticipated by exploiting the reactivity of difluorocarbene and primary amines to isocyanides or the formimidoyl fluoride intermediates.