A phosphine free, inorganic base free, one-pot tandem Mizoroki-Heck olefination/direct arylation/hydrogenation sequence, to give multicyclic alkylated heteroarenes

One-pot processes which facilitate a number of tandem reactions, represent an environmentally friendly approach to building molecular complexity. In addition, there are significant cost and time saving benefits. However, unearthing multiple reactions that display substrate, reagent and solvent compatibility across two or more reactions, is not straightforward. This is even more pronounced when using catalysts, which by their nature, are present in small amounts and thus susceptible to poisoning. Herein we describe a phosphine-free, inorganic base free, multi-step, one-pot reaction sequence which enables the rapid synthesis of complex, medicinally relevant heterocycles in excellent yields. This Pd-catalysed approach combines Heck olefination, C-H activation, and hydrogenation, and the same pre-catalyst is involved in the three mechanistically distinct processes. Quinolines as substrates are used in the main, but we also provide a neat extension to pyridines and simple aryl substrates. Deuterium (D-2) incorporation can be facilitated through use of the COware apparatus in the reduction step. Favourable mass productivity (MP), environmental impact factor (EF), solvent intensity (SI) and process mass intensity (PMI) values are reported. While the motivation to avoid problematic additives (inorganic base and P-ligands) and problematic solvent (DMA and NMP) was driven by a green agenda, the removal of reagents and additives in the context of one-pot strategies might also serve to reduce the bad actors and improve yields in one-pot processes.

Automated summary

One-pot processes offer an environmentally friendly and time-saving approach to building complex molecules. This study presents a phosphine-free, inorganic base free, multi-step, one-pot reaction sequence for the rapid synthesis of complex medicinally relevant heterocycles. The approach combines three distinct reactions using a single pre-catalyst and achieves excellent yields. The study also reports favorable mass productivity, environmental impact factor, solvent intensity, and process mass intensity values.