title: Double Reformatsky reaction: divergent synthesis of δ-hydroxy-β-ketoesters.
abstract: The double Reformatsky reaction, tandem addition of two molecules of zinc alkanoate to a carbonyl compound, and its synthetic application to a series of δ-hydroxy-β-ketoesters has been developed. The key to accelerate the double Reformatsky reaction is considered to be a complex-induced proximity effect of the in situ generated zinc alkoxide coordinated with the pyridyl group of the substrate or bidentate amines. A noteworthy feature of the reaction system is its high tolerance of functional groups due to the moderate nucleophilicity of organozinc reagents and the mild reaction conditions. Moreover, spectroscopic and crystallographic analyses of the zinc complex of the double Reformatsky product support the proposed mechanism of reaction site discrimination for ketones, aldehydes, nitriles, carboxylic acid anhydrides, and esters.
authors.affiliation: Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 2-17-85, Juso-honmachi, Yodogawa-ku, Osaka 532-8686, Japan. masahiro.mineno@takeda.com
authors.forename: Masahiro
authors.initials: M
authors.lastname: Mineno
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Sawai
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kanno
authors.forename: Naotaka
authors.initials: N
authors.lastname: Sawada
authors.forename: Hideya
authors.initials: H
authors.lastname: Mizufune
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000812:Anhydrides / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D004952:Esters / Q000138:chemical synthesis; D007659:Ketones / Q000138:chemical synthesis*; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry*
chemical_list: D000447:Aldehydes; D000588:Amines; D000812:Anhydrides; D002264:Carboxylic Acids; D004952:Esters; D007659:Ketones; D015032:Zinc