Unconventional Site Selectivity in Palladium-Catalyzed Cross-Couplings of Dichloroheteroarenes under Ligand-Controlled and Ligand-Free Systems

Abstract

Halides adjacent to nitrogen are conventionally more reactive in Pd-catalyzed cross-couplings of dihalogenated Nheteroarenes. However, a very sterically hindered N-heterocyclic carbene ligand is shown to promote room-temperature crosscoupling at C4 of 2,4-dichloropyridines with high selectivity (∼10:1). This work represents the first highly selective method with a broad scope for C4-coupling of these substrates where selectivity is clearly under ligand control. Under the optimized conditions, diverse substituted 2,4-dichloropyridines and related compounds undergo cross-coupling to form C4−C (sp2) and C4− C (sp3) bonds using organoboron, -zinc, and -magnesium reagents. The synthetic utility of this method is highlighted in multistep syntheses that combine C4-selective cross-coupling with subsequent nucleophilic aromatic substitution reactions. The majority of the products herein (71%) have not been previously reported, emphasizing the ability of this methodology to open up underexplored chemical space. Remarkably, we find that ligand-free "Jeffery" conditions enhance the C4 selectivity of Suzuki coupling by an order of magnitude (>99:1). These ligand-free conditions enable the first C5-selective cross-couplings of 2,5-dichloropyridine and 2,5-dichloropyrimidine.

The Road Less Traveled: Unconventional Site Selectivity in Palladium-Catalyzed Cross-Couplings of Dihalogenated N-Heteroarenes

“…Undesired “overarylation” is common in cross-coupling reactions of dihaloheteroarenes when using bulky NHC or biarylphosphine ligands, despite a 1:1 ratio of substrate to nucleophile. ,,, This trend is consistent with literature reports involving halogenated aromatic carbocycles. For example, Larosa et al found that IPent enables efficient “exhaustive arylation” of various dihalogenated arenes despite a deficit of nucleophile .…”

“…Recently, we further explored the role of ligand sterics on the site selectivity of Suzuki couplings of 2,4-dichloropyridine derivatives. 15,25 In agreement with earlier reports, a systematic analysis of ligand trends revealed a clear correlation between increased steric congestion around the metal center and increased selectivity for the distal C−Cl site (Scheme 4A). The highest selectivity for reaction at the distal position was achieved with bulky NHC ligands.…”

“…As discussed above, the relevance of catalyst speciation (mono- vs multinuclear) on site selectivity was discovered by Fairlamb in the context of couplings of 2,4-dibromopyridine . Our group later provided evidence that multinuclear Pd also gives unique selectivity in reactions of 2,4-dichloropyridine, as well as 2,5-dichloropyridine and -pyrimidine . Remarkably, it appears that multinuclear palladium has the potential to give much higher selectivities than systems in which selectivity is ligand-controlled.…”

Different Oxidative Addition Mechanisms for 12- and 14-Electron Palladium(0) Explain Ligand-Controlled Divergent Site Selectivity

“…The reported C4- and C5-cross-couplings of 2 , 3 , and 5 employ very sterically hindered electron-rich monodentate ligands. − To further evaluate ligand effects, we screened a number of monodentate phosphines and NHC ligands for the Suzuki coupling of 2 using Pd­(cod)­(CH 2 SiMe 3 ) 2 (Table ). There is a clear correlation between ligand sterics and the C4:C2 ratio for triarylphosphines (entries 1–4), alkylphosphines (entries 5–13), and NHCs (entries 14–18).…”

“…The use of QPhos gives modest C4-selectivity with 2 and high C5-selectivity with 5 (Scheme B) . Bulky NHC ligands ( 6 and IPr) can promote C4-selectivity with 2 and 3 and C5-selectivity with 5 (Scheme C,D). − There is currently no mechanistic rationale for these ligand-controlled deviations from the conventional selectivity . The absence of mechanistic understanding precludes rational catalyst design, and thus, cross-coupling reactions at distal C–X bonds remain unexplained curiosities.…”