Development of new palladium-catalyzed arylation reactions

Abstract

Penta-, tetra-, tri- and difluorobenzenes undergo intermolecular direct arylation with a wide range of aryihalides in high yield. Inverse reactivity is observed compared to the common electrophilic aromatic substitution pathway since electron-deficient, C-H acidic arenes react preferentially. Computational studies indicate that C-H bond cleavage occurs via a concerted carbon-palladium and carbon-hydrogen bond cleaving event involving a carbonate or a bromide ligand. The reactions are rapid, require only a slight excess of the perfluoroarene reagent, and utilize commercially available, air-stable catalyst precursors. A second generation catalyst was developed that enables the direct arylation of pentafluorobenzene with sterically encumbered aryl bromides and aryl chlorides. These reactions occur in high yield and under mild conditions. Notably, the reactions can be performed at 80°C in isopropyl acetate with a catalyst generated by the in situ mixing of Pd(OAc) 2 and S-Phos. The enhanced scope of these transformations should further reduce the need to use pentafluorophenylboronic acid in the construction of perfluoroarenes. From our mechanistic analysis of the direct arylation of perfluoroarenes, a palladium-pivalic acid co-catalyst system has been developed that exhibits unprecedented reactivity in direct arylations. This reactivity is illustrated with the first examples of high yielding direct metallation-arylation reactions of a completely unactivated arene, benzene, milder reaction conditions for the intramolecular direct arylation of simple arenes as well as the development of a novel direct alkylation reaction. Experimental and computational evidence indicates that the pivalate anion is a key component in the palladation/C-H bond breaking event, that it lowers the energy of C-H bond cleavage and acts as a catalytic proton shuttle from benzene to the stoichiometric carbonate base. In addition, the palladium-catalyzed direct arylation of aryl chlorides, bromides and iodides has been applied to the preparation of new aporphine analogues including C2 substituted aporphines by reaction with benzodioxole, pyridine N-oxide and pyrazine N-oxide. Successful application of direct arylation in these diversification reactions highlights its utility not only in convergent, but also in divergent synthesis. We also describe enantioselective syntheses of (R)-nornuciferine and (R)-nuciferine employing a catalytic asymmetric transfer hydrogenation in high yield and excellent enantiomeric excess.