Ligand-Controlled Regiodivergent Nickel-Catalyzed Annulation of Pyridones

• Published in: Angewandte Chemie International Edition Vol. 54; no. 2; pp. 633 - 637
• Main Authors: Donets, Pavel A., Cramer, Nicolai
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 07.01.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkaloids; Carbenes; Catalysis; Chemistry; Chemistry, Multidisciplinary; cyclization; CH activation; heterocycles; Ligands; Lupins; N-heterocyclic carbenes; Nickel; Nickel - chemistry; Olefins; Physical Sciences; Pyridones - chemistry; Science & Technology; Switches; Synthesis; nickel; 2-PYRIDONES; ISOMERIZATION; ARYLATION; INDOLIZIDINE; cyclization; DIRECT ALKYLATION; CH activation; CYCLIZATIONS; heterocycles; CAMPTOTHECIN; DERIVATIVES; OLEFIN COMPLEXES; N-heterocyclic carbenes; ALKALOIDS; CH activation
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201409669

The 1,6‐annulated 2‐pyridone motif is found in many biologically active compounds and its close relation to the indolizidine and quinolizidine alkaloid core makes it an attractive building block. A nickel‐catalyzed CH functionalization of 2‐pyridones and subsequent cyclization affords 1,6‐annulated 2‐pyridones by selective intramolecular olefin hydroarylation. The switch between the exo‐ and endo‐cyclization modes is controlled by two complementary sets of ligands. Irrespective of the ring size, the regioselectivity during the cyclization is under full catalyst control. Simple cyclooctadiene promotes an exo‐selective cyclization, whereas a bulky N‐heterocyclic carbene ligand results in an endo‐selective mode. The method was further applied in the synthesis of the lupin alkaloid cytisine. Nickeled and dimed: Nickel(0)‐catalyzed CH functionalization of 2‐pyridones and subsequent ligand‐controlled regioselective cyclization affords 1,6‐annulated 2‐pyridones. Cyclooctadiene (L1) selectively leads to exo cyclization, whereas the addition of a bulky N‐heterocyclic carbene ligand (L2) switches to the endo mode. The method was applied in the synthesis of the lupin alkaloid (±)‐cytisine. LA=Lewis acid.