Site-Selective Cross-Coupling of Polyhalogenated Arenes and Heteroarenes with Identical Halogen Groups

Abstract

Methods to functionalize arenes and heteroarenes in a site-selective manner are highly sought after for rapidly constructing value-added molecules of medicinal, agrochemical, and materials interest. One effective approach is the site-selective cross-coupling of polyhalogenated arenes bearing multiple, but identical, halogen groups. Such cross-coupling reactions have proven to be incredibly effective for site-selective functionalization. However, they also present formidable challenges due to the inherent similarities in the reactivities of the halogen substituents. In this Review, we discuss strategies for site-selective cross-couplings of polyhalogenated arenes and heteroarenes bearing identical halogens, beginning first with an overview of the reaction types that are more traditional in nature, such as electronically, sterically, and directing-group-controlled processes. Following these examples is a description of emerging strategies, which includes ligand- and additive/solvent-controlled reactions as well as photochemically initiated processes.

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

“…A popular method for their elaboration involves employing halogenated heteroarene substrates in cross-coupling reactions. Dihaloheteroarenes bearing two identical halides typically react with predictable selectivity at a C–X bond α to a heteroatom, when present (Scheme A) . However, the ability to invert selectivity can open up underexplored synthetic space.…”

A reactivity model for oxidative addition to palladium enables quantitative predictions for catalytic cross-coupling reactions

“…Bond strength arguments, often using calculated BDEs, are used to rationalize relative oxidative addition reactivity for different substrates, such as for site selectivity in multihalogenated systems. [59][60][61] In our initial model (Figure 2C, D), the IBSI term is essentially a step function: there are relatively narrow value distributions within the Ar-Br or Ar-Cl data sets, but a large gap between those data sets that reflects the weaker C-Br bond. Plotting a univariate correlation between IBSI C-X and GG ‡ OA for all three electrophile classes reveals a similarly tiered structure (Figure 2E).…”

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

“…From metalation and S N Ar to catalytic C–H functionalization by transition metals, regioselective elaborations of 6-membered nitrogen-containing heteroarenes have been the subject of extensive investigation. In discovery chemistry settings, dihalogenated azines are among the mainstay building blocks for the construction of di- or polysubstituted nitrogen heterocycles via iterative cross-coupling or other substitution methods …”

“…For heteroaromatic substrates bearing two or more halides, Pd-catalyzed cross-coupling reactions tend to proceed selectively, with a bias for reaction at sites adjacent to a heteroatom (Table ). This reactivity bias often enables straightforward synthesis of a single regioisomer. However, accessing target molecules with substitution patterns that are disfavored by cross-coupling is more challenging.…”

“…Multiple excellent reviews already provide a comprehensive picture of conventional selectivity . The focus of this Perspective is the minority of cases in which the regiochemical outcome deviates from the norm, some of which are more recent than existing reviews.…”