Photoinduced Cobalt Catalysis for the Reductive Coupling of Pyridines and Dienes Enabled by Paired Single-Electron Transfer.

Selective hydroarylation of dienes has potential to provide swift access to useful building blocks. However, most existing methods rely on dienes stabilised by an aromatic group and transmetallation or nucleophilic attack steps require electron-rich aryl coupling partners. As such, there are few examples which tolerate wide-spread heteroarenes such as pyridine. Whilst allylic C-H functionalisation could be considered an alternative approach, the positional selectivity of unsymmetrical substrates is hard to control. Here, we report a general approach for selective hydropyridylation of dienes under mild conditions using metal catalysed hydrogen-atom transfer. Photoinduced, reductive conditions enable simultaneous formation of a cobalt-hydride catalyst and the persistent radical of easily-synthesised pyridyl phosphonium salts. This facilitates selective coupling of dienes in a traceless manner at the C4-position of a wide-range of pyridine substrates. The mildness of the method is underscored by its functional-group tolerance and demonstrated by applications in late-stage functionalisation. Based on a combination of experimental and computational studies, we propose a mechanistic pathway which proceeds through non-reversible hydrogen-atom transfer (HAT) from a cobalt hydride species which is uniquely selective for dienes in the presence of other olefins due to a much higher relative barrier associated with olefin HAT.

Cross-Coupling of α-Carbonyl Sulfoxonium Ylides with C-H Bonds.

The functionalization of carbon-hydrogen bonds in non-nucleophilic substrates using α-carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross-coupling reactions of sulfoxonium ylides with C(sp2 )-H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C-H activation, migratory insertion of the ylide into the carbon-metal bond, and protodemetalation, the last step being turnover-limiting. The method is applied to the synthesis of benz[c]acridines when allied to an iridium-catalyzed dehydrative cyclization.

Comparison of free-radical inhibiting antioxidant properties of carvedilol and its phenolic metabolites.

Carvedilol is a widely prescribed drug for the treatment of heart failure and the prevention of associated ventricular arrhythmias. It has also been reported to function as a biological antioxidant via hydrogen atom transfer from its carbazole N-H moiety to chain-propagating radicals. Metabolites of the drug include phenolic derivatives, such as 3-hydroxy-, 4'-hydroxy- and 5'-hydroxycarvedilol, which are also potential antioxidants. A comparison of the radical-inhibiting activities of the parent drug and the three metabolites was carried out in two separate assays. In the first, hydrogen atom transfer from these four compounds to the stable radical DPPH was measured by the decrease in the UV-visible absorption at 515 nm of the latter. The known radical inhibitors BHT, 4-hydroxycarbazole and α-tocopherol were employed as benchmarks in parallel experiments. In the second assay, inhibition of the photoinduced free-radical 1,2-addition of Se-phenyl p-tolueneselenosulfonate to cyclopropylacetylene, along with competing ring-opening of the cyclopropane ring, was monitored by 1H NMR spectroscopy in the presence of the carvedilol-based and benchmark antioxidants. In both assays, carvedilol displayed negligible antioxidant activity, while the three metabolites all proved superior radical inhibitors to BHT, with radical-quenching abilities in the order 3-hydroxy- > 5'-hydroxy > 4'-hydroxycarvedilol. Among the metabolites, 3-hydroxycarvedilol displayed even stronger activity in both assays than α-tocopherol, the best of the benchmark antioxidants. These results suggest that the radical-inhibiting antioxidant properties that have been attributed to carvedilol are largely or exclusively due to its metabolites and not to the parent drug itself.

Regioselective Synthesis of 3-Hydroxy-4,5-alkyl-Substituted Pyridines Using 1,3-Enynes as Alkynes Surrogates.

The poor regioselectivity of the [4 + 2] cycloaddition of 3-azetidinones with internal alkynes bearing two alkyl substituents via nickel-catalyzed carbon-carbon activation is addressed using 1,3-enynes as substrates. The judicious choice of substitution on the enyne enables complementary access to each regioisomer of 3-hydroxy-4,5-alkyl-substituted pyridines, which are important building blocks in medicinal chemistry endeavors.