Improving the sustainability of the ruthenium-catalysed N-directed C-H arylation of arenes with aryl halides.

Direct C-H functionalisation methodologies represent an opportunity to improve the overall 'green' credentials of organic coupling reactions, improving atom economy and reducing overall step count. Despite this, these reactions frequently run under reaction conditions that leave room for improved sustainability. Herein, we describe a recent advance in our ruthenium-catalysed C-H arylation methodology that aims to address some of the environmental impacts associated with this procedure, including solvent choice, reaction temperature, reaction time, and loading of the ruthenium catalyst. We believe that our findings demonstrate a reaction with improved environmental credentials and showcase it on a multi-gram scale within an industrial setting.

Ruthenium-Catalyzed Monoselective C-H Methylation and d 3-Methylation of Arenes.

Site-selective installation of C-Me bonds remains a powerful and sought-after tool to alter the chemical and pharmacological properties of a molecule. Direct C-H functionalization provides an attractive means of achieving this transformation. Such protocols, however, typically utilize harsh conditions and hazardous methylating agents with poor applicability toward late-stage functionalization. Furthermore, highly monoselective methylation protocols remain scarce. Herein, we report an efficient monoselective, directed ortho-methylation of arenes using N,N,N-trimethylanilinium salts as noncarcinogenic, bench-stable methylating agents. We extend this protocol to d 3-methylation in addition to the late-stage functionalization of pharmaceutically active compounds. Detailed kinetic studies indicate the rate-limiting in situ formation of MeI is integral to the observed reactivity.