One-Pot Cross-Coupling/C-H Functionalization Reactions: Quinoline as a Substrate and Ligand through N-Pd Interaction.

Herein, we report a one-pot process that marries mechanistically distinct, traditional cross-coupling reactions with C-H functionalization using the same precatalyst. The reactions proceed in yields of up to 95%, in air, and require no extraneous ligand. The reactions are thought to be facilitated by harnessing the substrate quinoline as an N-ligand, and evidence of the palladium-quinoline interaction is provided by 1H-15N HMBC NMR spectroscopy and X-ray crystallographic structures. Application of the methodology is demonstrated by the quick formation of fluorescent, π-extended frameworks.

Competition between N and O: use of diazine N-oxides as a test case for the Marcus theory rationale for ambident reactivity.

The preferred site of alkylation of diazine N-oxides by representative hard and soft alkylating agents was established conclusively using the 1H-15N HMBC NMR technique in combination with other NMR spectroscopic methods. Alkylation of pyrazine N-oxides (1 and 2) occurs preferentially on nitrogen regardless of the alkylating agent employed, while O-methylation of pyrimidine N-oxide (3) is favoured in its reaction with MeOTf. As these outcomes cannot be explained in the context of the hard/soft acid/base (HSAB) principle, we have instead turned to Marcus theory to rationalise these results. Marcus intrinsic barriers (ΔG ‡ 0) and Δr G° values were calculated at the DLPNO-CCSD(T)/def2-TZVPPD/SMD//M06-2X-D3/6-311+G(d,p)/SMD level of theory for methylation reactions of 1 and 3 by MeI and MeOTf, and used to derive Gibbs energies of activation (ΔG ‡) for the processes of N- and O-methylation, respectively. These values, as well as those derived directly from the DFT calculations, closely reproduce the observed experimental N- vs. O-alkylation selectivities for methylation reactions of 1 and 3, indicating that Marcus theory can be used in a semi-quantitative manner to understand how the activation barriers for these reactions are constructed. It was found that N-alkylation of 1 is favoured due to the dominant contribution of Δr G° to the activation barrier in this case, while O-alkylation of 3 is favoured due to the dominant contribution of the intrinsic barrier (ΔG ‡ 0) for this process. These results are of profound significance in understanding the outcomes of reactions of ambident reactants in general.

Cyclization of 4-Phenoxy-2-coumarins and 2-Pyrones via a Double C-H Activation.

Aryl-heteroaryl coupling via double C-H activation is a powerful transformation that avoids the installation of activating groups. A double C-H activation of privileged biological scaffolds, 2-coumarins and 2-pyrones, is reported. Despite the rich chemistry of these molecular frameworks, the yields are very good. Excellent regioselectivity was achieved on the pyrones. This methodology was applied to the synthesis of flemichapparin C in three steps. Isotope effect experiments were carried out, and a mechanism is proposed.

A study of the norcaradiene-cycloheptatriene equilibrium in a series of azulenones by NMR spectroscopy; the impact of substitution on the position of equilibrium.

A systematic investigation of the influence of substitution at positions C-2 and C-3 on the azulenone skeleton, based on NMR characterisation, is discussed with particular focus on the impact of the steric and electronic characteristics of substituents on the position of the norcaradiene-cycloheptatriene (NCD-CHT) equilibrium. Variable temperature (VT) NMR studies, undertaken to enable the resolution of signals for the equilibrating valence tautomers revealed, in addition, interesting shifts in the equilibrium.

Recent advances in aryl-aryl bond formation by direct arylation.

The abundance of the biaryl structural motif in natural products, in biologically active molecules and in materials chemistry has positioned aryl-aryl (Ar-Ar) bond formation high on the agenda of synthetic chemists. For decades well-known reactions such as the Mizoroki-Heck and Suzuki-Miyaura have been the methods of choice to furnish biaryls. More recently, however, alternative methods, most notably direct arylation via C-H activation, have become the focus of many research groups. Compared to traditional methods, direct arylation affords Ar-Ar compounds in fewer steps by removing the need for prefunctionalisation. Furthermore, given that either one or two hydrogens are targeted, less waste and good atom economy are features of this methodology. This critical review covers, in the main part, reports from January 1, 2006, to October 22, 2008 (117 references).