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

Abstract

The vast majority (≥90%) of literature reports agree on the regiochemical outcomes of Pd-catalyzed cross-coupling reactions for most classes of dihalogenated N-heteroarenes. Despite a well-established mechanistic rationale for typical selectivity, several examples reveal that changes to the catalyst can switch site selectivity, leading to the unconventional product. In this Perspective, we survey these unusual cases in which divergent selectivity is controlled by ligands or catalyst speciation. In some cases, the mechanistic origin of inverted selectivity has been established, but in others the mechanism remains unknown. This Perspective concludes with a discussion of remaining challenges and opportunities for the field of site-selective cross-coupling. These include developing a better understanding of oxidative addition mechanisms, understanding the role of catalyst speciation on selectivity, establishing an explanation for the influence of ring substituents on regiochemical outcome, inverting selectivity for some “stubborn” classes of substrates, and minimizing unwanted over-reaction of di- and polyhalogenated substrates.

Triflate‐Selective Suzuki Cross‐Coupling of Chloro‐ and Bromoaryl Triflates Under Ligand‐Free Conditions

“…The optimized conditions also lead to exclusive cross‐coupling at the C5 triflate of 2‐chloro‐5‐trifloylpyridine ( 11 ). This result is notable because products like 11 are difficult to access from 2,5‐dichloropyridine: all reported Suzuki couplings of the dichlorinated substrate in the presence of ligands lead to selective reaction at C2 [14,15] . Aryl chlorides are profoundly inert under the optimized ligand‐free conditions.…”

Heterocyclic Suzuki–Miyaura coupling reaction of metalla-aromatics and mechanistic analysis of site selectivity

“…The effect of additional phosphine ligands on the reaction has been probed systematically. 13 We found that the reactions have been restrained by adding additional phosphines, even PPh 3 ligands, under the reaction condition in entry 5 (entry 7, see Section S29 in the ESI † for further details). We speculate that the trace decomposition of the metalla-aromatic substrates would provide sufficient PPh 3 ligands to form catalytically active Pd species.…”

Catalyst-Controlled Enantioselective and Regiodivergent Addition of Aryl Boron Nucleophiles to N-Alkyl Nicotinate Salts

“…Site-selective functionalization of molecules that contain multiple reactive sites remains a significant challenge in organic synthesis. − Along with this challenge comes the opportunity that achieving site-selective functionalization could enable synthesis of a variety of molecules from a small subset of starting materials. While selective functionalization of electrophiles that contain two reactive sites has been significantly developed (e.g., 1,2 vs 1,4 addition to α,β-unsaturated carbonyl compounds), development of methods to functionalize extended π systems has lagged.…”

“…In this context, pyridinium salts are multident electrophiles that, in the presence of nucleophiles, can undergo (1,2), (1,4), or (1,6) addition to afford the corresponding dihydropyridines (DHPs). 8−31 These scaffolds are useful intermediates for the preparation of nonaromatic nitrogen heterocycles (Figure 1A).…”