James Alan Morris

Ligand-Promoted C3-Selective Arylation of Pyridines with Pd Catalysts: Gram-Scale Synthesis of (±)-Preclamol

The first example of Pd-catalyzed, C3-selective arylation of unprotected pyridines has been developed by employing a catalytic system consisting of Pd(OAc)(2) and 1,10-phenanthroline. This protocol provides an expeditious route to an important class of 3-arylpyridines and 3-arylpiperidines frequently found in bioactive compounds. A brief synthesis of the drug molecule (±)-preclamol is also reported.

Iridium-catalyzed C–H borylation of quinolines and unsymmetrical 1,2-disubstituted benzenes: insights into steric and electronic effects on selectivity

Borylation of quinolines provides an attractive method for the late-stage functionalization of this important heterocycle. The regiochemistry of this reaction is dominated by steric factors but, by undertaking reactions at room temperature, an underlying electronic selectivity becomes apparent, as exemplified by the comparative reactions of 7-halo-2-methylquinoline and 2,7-dimethylquinoline which afford variable amounts of the 5- and 4-borylated products. Similar electronic selectivities are observed for nonsymmetrical 1,2-disubstituted benzenes. The site of borylation can be simply estimated by analysis of the 1H NMR spectrum of the starting material with preferential borylation occurring at the site of the most deshielded sterically accessible hydrogen or carbon atom. Such effects can be linked with C–H acidity. Whilst DFT calculations of the pKa for the C–H bond show good correlation with the observed selectivity, small differences suggest that related alternative, but much more computationally demanding values, such as the M–C bond strength, may be better quantitative predictors of selectivity.

Palladium-catalyzed benzylic arylation of 2-methyl azaarenes.

A palladium-catalyzed benzylic sp(3) direct arylation of electron-deficient heterocycles is reported. The method described enables the introduction of electron-rich and -poor aromatics at the benzylic position of heterocycles without the need for preactivation or the use of directing groups.

A robust protocol for Pd(II)-catalyzed C-3 arylation of (1H) indazoles and pyrazoles: total synthesis of nigellidine hydrobromide

C3-arylated indazole and pyrazoles are privileged structural motifs in agrochemicals and pharmaceuticals. C-3 C-H arylation of (1H) indazole and pyrazole has been a significant challenge due to the poor reactivity of the C-3 position. Herein, we report a practical Pd(II)/Phen catalyst and conditions for direct C-3 arylation of indazole and pyrazole with ArI or ArBr without using Ag additives as halide scavengers. The use of toluene, chlorobenzene, trifluoromethylbenzene and mesitylene as the solvent was found to be crucial for the selectivity and reactivity. We further demonstrate the robustness of this protocol through the first total synthesis of Nigellidine hydrobromide as well as expedient preparation of heterocycles structurally related to pesticides and drug molecules.

Iodide as an Activating Agent for Acid Chlorides in Acylation Reactions

Acid chlorides can be activated using a simple iodide source to undergo nucleophilic attack from a variety of relatively weak nucleophiles. These include Friedel-Crafts acylation of N-methylpyrroles, N-acylation of sulfonamides, and acylation reactions of hindered phenol derivatives. The reaction is believed to proceed through a transient acid iodide intermediate.

Alternative Hydrogen Source for Asymmetric Transfer Hydrogenation in the Reduction of Ketones

cis‐1,4‐Butenediol is shown to be a highly active hydrogen source for asymmetric transfer hydrogenation in the reduction of ketones. With the use of a ruthenium catalyst, cis‐1,4‐butenediol is isomerised and subsequently oxidised to a lactone as an irreversible step, which provides the driving force for the asymmetric reduction of ketones.