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The use of ligands to control regioselectivity in transition-metal-catalyzed C-H activation/functionalization is a highly desirable but challenging task. Recently, Itami et al. reported an important finding relating to Pd-catalyzed ligand-controlled α/β-selective C-H arylation of thiophenes. Specifically, the use of the 2,2'-bipyridyl ligand resulted in α-arylation, whereas the use of the bulky fluorinated phosphine ligand P[OCH(CF(3))(2)](3) resulted in β-arylation. Understanding of this surprising ligand-controlled α/β-selectivity could provide important insights into the development of more efficient catalyst systems for selective C-H arylation, and so we carried out a detailed computational study on the problem with use of density functional theory methods. Three mechanistic possibilities--S(E)Ar and migration, metalation/deprotonation, and Heck-type arylation mechanisms--were examined. The results showed that the S(E)Ar and migration mechanism might not be plausible, because the key Wheland intermediates could not be obtained. On the other hand, our study indicated that the metalation/deprotonation and Heck-type arylation mechanisms were both involved in Itami's reactions. In the metalation/deprotonation pathway the α-selective product (C5-product) was preferred, whereas in the Heck-type arylation mechanism the β-selective product (C4-product) was favored. The ligands played crucial roles in tuning the relative barriers of the two different pathways. In the 2,2'-bipyridyl-assisted system, the metalation/deprotonation pathway was energetically advantageous, leading to α-selectivity. In the P[OCH(CF(3))(2)](3)-assisted system, on the other hand, the Heck-type arylation mechanism was kinetically favored, leading to β-selectivity. An interesting finding was that P[OCH(CF(3))(2)](3) could produce a C-H···O hydrogen bond in the catalyst system, which was crucial for stabilization of the Heck-type transition state. In comparison, this C-H···O hydrogen bond was absent with the other phosphine ligands [i.e., P(OMe)(3), PPh(3), PCy(3)] and these phosphine ligands therefore favored the metalation/deprotonation pathway leading to α-selectivity. Furthermore, in this study we have provided theoretical evidence showing that the Heck-type arylation reaction could proceed through an anti-β-hydride elimination process., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Transition-metal-catalyzed decarboxylative coupling presents a new and important direction in synthetic chemistry. Mechanistic studies on decarboxylative coupling not only improve the understanding of the newly discovered transformations, but also may have valuable implications for the development of more effective catalyst systems. In this work, a comprehensive theoretical study was conducted on the mechanism of Myers' Pd-catalyzed decarboxylative Heck reaction. The catalytic cycle was found to comprise four steps: decarboxylation, olefin insertion, beta-hydride elimination, and catalyst regeneration. Decarboxylation was the rate-limiting step, and it proceeded through a dissociative pathway in which Pd(II) mediated the extrusion of CO(2) from an aromatic carboxylic acid to form a Pd(II)-aryl intermediate. Further analysis was conducted on the factors that might control the efficiency of Myers' decarboxylative Heck reaction. These factors included Pd salts, ligands, acid substrates, and metals. (1) Regarding Pd salts, PdCl(2) and PdBr(2) were worse catalysts than Pd(TFA)(2), because the exchange of Cl or Br by a carboxylate from Pd was thermodynamically unfavorable. (2) Regarding ligands, DMSO provided the best compromise between carboxyl exchange and decarboxylation. Phosphines and N-heterocarbenes disfavored decarboxylation because of their electron richness, whereas pyridine ligands disfavored carboxyl exchange. (3) Regarding acid substrates, a good correlation was observed between the energy barrier of R-COOH decarboxylation and the R-H acidity. Substituted benzoic acids showed deviation from the correlation because of the involvement of pi(substituent)-sigma(C(ipso)-Pd) interaction. (4) Regarding metals, Ni and Pt were worse catalysts than Pd because of the less favorable carboxyl exchange and/or DMSO removal steps in Ni and Pt catalysis.

N,O-Bidentate compounds were systematically evaluated as phosphine-free ligands for Pd-catalyzed C-C bond-formation reactions through kinetic measurements. Pd(quinoline-8-carboxylate)2 was identified as one of the most efficient, yet still low-priced, phosphine-free catalysts for Heck as well as Suzuki reactions of unactivated aryl bromides with high turnover numbers up to ca. 10,000.

N,N-Dimethyl-beta-alanine was found to be a more powerful phosphine-free ligand than the previously reported ligand, N,N-dimethylglycine, in the Pd-catalyzed Heck reaction for a variety of aryl bromides, aryl iodides, and activated aryl chlorides with a practical turnover number of 10(3). Both kinetic and theoretical studies suggested that N,N-dimethyl-beta-alanine led to faster oxidative addition of an aryl halide to Pd than N,N-dimethylglycine. [reaction: see text]