Synthesis of Aminopyridines and Aminopyridones by Cobalt-Catalyzed [2+2+2] Cycloadditions Involving Yne-Ynamides: Scope, Limitations, and Mechanistic Insights

• Published in: Chemistry : a European journal 2012-04, Vol.18 (14), p.4337-4344
• Main Authors: Garcia, Pierre, Evanno, Yannick, George, Pascal, Sevrin, Mireille, Ricci, Gino, Malacria, Max, Aubert, Corinne, Gandon, Vincent
• Format: Article
• Language: English
• Subjects: alkynes; Alkynes - chemistry; Amides - chemistry; Aminopyridines - chemical synthesis; Aminopyridines - chemistry; Aromatic compounds; Catalysis; Chemical Sciences; Chemistry; Cobalt; Cobalt - chemistry; Cyclization; Cycloaddition; Insertion; Molecular Structure; Nitriles; Nitriles - chemistry; nitrogen heterocycles; Organic chemistry; Pathways; Pyridines; Pyridones - chemical synthesis; Pyridones - chemistry; reaction mechanisms; reactive intermediates; Stereoisomerism; Synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201103906

An in‐depth study of the cobalt‐catalyzed [2+2+2] cycloaddition between yne‐ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal‐catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron‐deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne‐ynamide allows the regioselectivity to be switched toward 3‐ or 4‐aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne‐ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3‐aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4‐aminopyridines arise from an insertion pathway. Cobalt directs: Cobalt‐catalyzed [2+2+2] cycloadditions between yne‐ynamides and nitriles affords 3‐ and 4‐aminopyridines regioselectively (see scheme). The precatalyst [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) allows the use of both electron‐rich and ‐poor nitriles. DFT suggests that 3‐aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4‐aminopyridines seem to arise from an insertion pathway.