Synthetic and mechanistic strategies to achieve unconventional site-selectivity in cross-couplings of dihalo-heteroarenes

Abstract

Pd-catalyzed cross-couplings rank among the most powerful methods for constructing substituted biaryls, polyaryls, and heteroarenes. Frequently, di- or polyhalogenated (hetero)arenes are employed as starting materials in cross-couplings to access products with increased structural complexity via multiple cross-coupling or substitution steps. N-heteroarenes bearing multiple reactive handles--such as halides, are of particular interest as starting materials since their cross- coupled products can be medicinally relevant. Non-symmetrical dihalogenated N-heteroarenes typically exhibit a site-selectivity bias for C-X bonds which are adjacent to at least one heteroatom in Pd-catalyzed cross-couplings. However, some Pd catalysts--particularly those with hindered ligands, promote atypical selectivity at distal C-X bonds of 2,X-dichloropyridines and related heterocycles during the selectivity-determining oxidative addition step. This dissertation explores the mechanistic origins of these ligand trends and emphasizes the critical importance of Pd's ligation state--either mono (PdL) or bis (PdL 2), in controlling the site of oxidative addition. Ligation state is also relevant when selecting for the products of mono- vs difunctionalization in cross-couplings of dihalogenated substrates, since bisligated 14 e - Pd dissociates quickly from the monofunctionalized intermediate after an initial cross-coupling cycle, whereas monoligated 12 e - Pd is slow to dissociate and may "ring-walk" to the remaining reactive site(s). Additionally, this dissertation explores alternative methods to access minor regioisomers in cross-couplings of dichloro-azines. One approach involves ligand-free conditions where atypical site-selectivity at dichloropyridines and dichloropyrimidines arises from a change in Pd's speciation from mono- to multinuclearity. Another approach employs a thiolation/Liebeskind-Srogl arylation sequence to achieve site-selectivity which is orthogonal to that of Suzuki-Miyaura couplings.