title: Ruthenium-Catalyzed Formal Dehydrative [4 + 2] Cycloaddition of Enamides and Alkynes for the Synthesis of Highly Substituted Pyridines: Reaction Development and Mechanistic Study.
abstract: Reported herein is a ruthenium-catalyzed formal dehydrative [4 + 2] cycloaddition of enamides and alkynes, representing a mild and economic protocol for the construction of highly substituted pyridines. Notably, the features of broad substrate scope, high efficiency, good functional group tolerance, and excellent regioselectivities were observed for this reaction. Density functional theory (DFT) calculations and experiments have been carried out to understand the mechanism and regiochemistry. DFT calculations suggested that this formal dehydrative [4 + 2] reaction starts with a concerted metalation deprotonation of the enamide by the acetate group in the Ru catalyst, which generates a six-membered ruthenacycle intermediate. Then alkyne inserts into the Ru-C bond of the six-membered ruthenacycle, giving rise to an eight-membered ruthenacycle intermediate. The carbonyl group (which comes originally from the enamide substrate and is coordinated to the Ru center in the eight-membered ruthenacycle intermediate) then inserts into the Ru-C bond to give an intermediate, which produces the final pyridine product through further dehydration. Alkyne insertion step is a regio-determining step and prefers to have the aryl groups of the used alkynes stay away from the catalyst in order to avoid repulsion of aryl group with the enamide moiety in the six-membered ruthenacycle and to keep the conjugation between the aryl group and the triple C-C bond of the alkynes. Consequently, the aryl groups of the used alkynes are in the β-position of the final pyridines, and the present reaction has high regioselectivity.
authors.affiliation: †Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jicheng
authors.initials: J
authors.lastname: Wu
authors.affiliation: ‡Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry, Peking University, Beijing 100871, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Xu
authors.affiliation: ‡Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry, Peking University, Beijing 100871, China.
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Yu
authors.affiliation: †Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D002384:Catalysis; D061565:Cycloaddition Reaction; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry*; D011789:Quantum Theory; D012428:Ruthenium / Q000737:chemistry*
chemical_list: D000480:Alkynes; D000577:Amides; D011725:Pyridines; D012428:Ruthenium; C023666:pyridine