ja1048847_si_001.pdf (3.75 MB)

Intramolecular Palladium-Catalyzed Alkane C−H Arylation from Aryl Chlorides

Download (3.75 MB)
journal contribution
posted on 11.08.2010, 00:00 by Sophie Rousseaux, Michaël Davi, Julien Sofack-Kreutzer, Cathleen Pierre, Christos E. Kefalidis, Eric Clot, Keith Fagnou, Olivier Baudoin
The first examples of efficient and general palladium-catalyzed intramolecular C(sp3)−H arylation of (hetero)aryl chlorides, giving rise to a variety of valuable cyclobutarenes, indanes, indolines, dihydrobenzofurans, and indanones, are described. The use of aryl and heteroaryl chlorides significantly improves the scope of C(sp3)−H arylation by facilitating the preparation of reaction substrates. Careful optimization studies have shown that the palladium ligand and the base/solvent combination are crucial to obtaining the desired class of product in high yields. Overall, three sets of reaction conditions employing PtBu3, PCyp3, or PCy3 as the palladium ligand and K2CO3/DMF or Cs2CO3/pivalic acid/mesitylene as the base/solvent combination allowed five different classes of products to be accessed using this methodology. In total, more than 40 examples of C−H arylation have been performed successfully. When several types of C(sp3)−H bond were present in the substrate, the arylation was found to occur regioselectively at primary C−H bonds vs secondary or tertiary positions. In addition, in the presence of several primary C−H bonds, selectivity trends correlate with the size of the palladacyclic intermediate, with five-membered rings being favored over six- and seven-membered rings. Regio- and diastereoselectivity issues were studied computationally in the prototypal case of indane formation. DFT(B3PW91) calculations demonstrated that C−H activation is the rate-determining step and that the creation of a C−H agostic interaction, increasing the acidity of a geminal C−H bond, is a critical factor for the regiochemistry control.