title: Domino Acylation/Diels-Alder Synthesis of N-Alkyl-octahydroisoquinolin-1-one-8-carboxylic Acids under Low-Solvent Conditions.
abstract: The development of the domino reaction between an aminoethyl-substituted diene and maleic anhydride to afford an N-substituted octahydroisoquinolin-1-one is described. A typical procedure involves the treatment of a 1-aminoethyl-substituted butadiene with maleic anhydride at 0 °C to room temperature for 20 min under low-solvent conditions, which affords a series of isoquinolinone carboxylic acids in moderate to excellent yields. NMR monitoring suggested that the reaction proceeded via an initial acylation step followed by an intramolecular Diels-Alder reaction. For the latter step, a significant rate difference was observed depending on whether the amino group was substituted by a phenyl or an alkyl (usually benzyl) substituent, with the former noted by NMR to be substantially slower. The Diels-Alder step was studied by density functional theory (DFT) methods, leading to the conclusion that the degree of preorganization in the starting acylated intermediate had the largest effect on the reaction barriers. In addition, the effect of electronics on the aromatic ring in N-phenyl substrates was studied computationally and experimentally. Overall, this protocol proved considerably more amenable to scale up compared to earlier methods by eliminating the requirement of microwave batch chemistry for this reaction as well as significantly reducing the quantity of solvent.
authors.affiliation: †Department of Medicinal Chemistry, University of Kansas, Delbert M. Shankel Structural Biology Center, 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Slauson
authors.affiliation: ‡Department of Chemistry, University of California at Davis, Davis, California 95616, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Pemberton
authors.affiliation: †Department of Medicinal Chemistry, University of Kansas, Delbert M. Shankel Structural Biology Center, 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Partha
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: ‡Department of Chemistry, University of California at Davis, Davis, California 95616, United States.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Tantillo
authors.affiliation: †Department of Medicinal Chemistry, University of Kansas, Delbert M. Shankel Structural Biology Center, 2034 Becker Drive, Lawrence, Kansas 66047, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
mesh_terms: D000215:Acylation; D002264:Carboxylic Acids / Q000737:chemistry*; D002384:Catalysis; D061565:Cycloaddition Reaction; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D012997:Solvents / Q000737:chemistry*
chemical_list: D002264:Carboxylic Acids; D007546:Isoquinolines; D012997:Solvents