Palladium-catalysis to dihydrodibenzoazepine derivatives: synthesis, structure and theoretical calculations

IND-OR-08 Palladium-catalysis to Dihydrodibenzoazepine Derivatives: Synthesis, Structure and Theoretical Calculations In the framework of our research aimed at developing efficient methods for the construction of complex molecules through a series of metal-controlled steps, starting from a pool of simple molecules [1] we have worked out a one-pot process for the synthesis of dihydrodibenzoazepines, an important class of seven-membered heterocycles with pharmacological activity [2]. The process consists of the reaction of one molecule of aryl iodide, one of a bromoaniline and one of norbornene at 105 °C in DMF under the catalytic action of palladium(0)/triarylphosphine. Several steps occur, including the initial oxidative addition of the aryl halide to palladium(0), norbornene insertion, palladacycle formation, new oxidative addition, this time involving bromoaniline, o-aminoaryl migration onto the norbornyl site of the palladacycle, azepine ring closure by reaction of the amino group with the palladium-bonded arene carbon [3]. All steps occur chemo- and regio-selectively and are compatible with a variety of substituents. Thus it has been possible to obtain compounds of the type reported in Figure 1 (R1 = H, alkyl, alkoxy, R2 = H, alkyl, Cl, carbalkoxy, R3 = alkyl, Cl, F) in high yields. The structure of two members of this class (R1 = Me, R2, R3 = H; R1 = Me, R2 = 7-Me, R3 = H) has been determined by single-crystal X-ray diffraction [4]. Theoretical calculations indicate the critical role played by the chelating amino group in directing the reaction pathway to the seven-membered ring formation [5]. [1] M.Catellani, E.Motti, and N.Della Ca’, Acc.Chem.Res., 41, 2008, 1512. [2] a) D.Tsvelikhovsky, and S.L.Buchwald, J.Am.Chem.Soc., 132, 2010, 14048 and references therein. [3] G.Maestri, E.Motti, N.Della Ca’, M.Malacria, E.Derat, and M.Catellani, J.Am.Chem.Soc., 133, 2011, 8574. [4] B.M.Aresta, M.Catellani, N.Della Ca’, C.Cuocci, S. Maggi, E. Motti, this Conference. [5] N.Della Ca’, G.Maestri, M.Malacria, E.Derat, and M.Catellani, submitted.