Transition-Metal and Brønsted Acid co-Catalysed Tandem Transformations

Abstract

Transition metal catalysed tandem transformations based on double-bond migration have enabled distal functionalization by merging multiple reaction steps. This methodology stands out as a stepeconomical approach in rapidly assembling molecular complexity. In the presented doctoral thesis, it provided an impetus not only to discover new tandem transformations but also to develop non precious transition metal-based alternatives for existing transformations. The project comprises three parts. First, the reactivity of palladium hydride complex in a novel CS bond formation methodology was explored. Branched benzylic thioethers were synthesized from corresponding allyl arenes in a double bond migration/hydrothiolation sequence. This was accompanied by reaction kinetics, isotope labelling and NMR investigation. Also, a remote C-S bond formation strategy was disclosed for the first time. In the second part, a structurally simple nickel-hydride was used along with a Brønsted acid to append a pyran ring onto heterocyclic scaffolds. The driving force behind this transformation is the generation of ‘inium’-cation by the synergistic action of a metal-hydride and Brønsted acid. Several classes of heterocycles such as tetrahydropyran-indoles, oxazine-indoles, isochromans and cyclic hemiaminals could be targeted. The double bond migration/cyclization could be carried out with catalyst loading as low as 0.075 mol%. Finally, to further explore the synthetic potential of nickel-hydride, a strategy for O-allyl deprotection was developed. Several O-allylated phenols with varying electronic bias as well as O-allylated aliphatic alcohols and amides displayed compatibility with the optimized reaction conditions.