Sterically controlled isodesmic late-stage C-H iodination of arenes.

Aryl iodides are key motifs in organic chemistry due to their versatility as linchpins in metal-mediated cross-coupling reactions for synthesis and drug discovery. These scaffolds are typically prepared indirectly from prefunctionalized starting materials or via electrophilic aromatic iodination protocols. These methods are limited to specific regioisomers by their inherent selectivities and/or the availability of the required starting materials. Herein, we describe the sterically controlled iodination of arenes through an isodesmic C-H/C-I bond metathesis approach enabled by our dual ligand-based catalysts for arene-limited nondirected C-H activation. The protocol gives direct access to a complementary product spectrum with respect to traditional methods. Its synthetic utility is demonstrated by a broad scope and the suitability for late-stage modification.

Palladium-Catalyzed Nondirected Late-Stage C-H Deuteration of Arenes.

We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labeling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, among other applications, will prove useful as a tool in drug development processes and for mechanistic studies.

General Pyrrolidine Synthesis via Iridium-Catalyzed Reductive Azomethine Ylide Generation from Tertiary Amides and Lactams.

An iridium-catalyzed reductive generation of both stabilized and unstabilized azomethine ylides and their application to functionalized pyrrolidine synthesis via [3 + 2] dipolar cycloaddition reactions is described. Proceeding under mild reaction conditions from both amide and lactam precursors possessing a suitably positioned electron-withdrawing or a trimethylsilyl group, using 1 mol% Vaska's complex [IrCl(CO)(PPh3)2] and tetramethyldisiloxane (TMDS) as a terminal reductant, a broad range of (un)stabilized azomethine ylides were accessible. Subsequent regio- and diastereoselective, inter- and intramolecular dipolar cycloaddition reactions with variously substituted electron-deficient alkenes enabled ready and efficient access to structurally complex pyrrolidine architectures. Density functional theory (DFT) calculations of the dipolar cycloaddition reactions uncovered an intimate balance between asynchronicity and interaction energies of transition structures, which ultimately control the unusual selectivities observed in certain cases.

Mechanism of the Arene-Limited Nondirected C-H Activation of Arenes with Palladium*.

Recently palladium catalysts have been discovered that enable the directing-group-free C-H activation of arenes without requiring an excess of the arene substrate, thereby enabling methods for the late-stage modification of complex organic molecules. The key to success has been the use of two complementary ligands, an N-acyl amino acid and an N-heterocycle. Detailed experimental and computational mechanistic studies on the dual-ligand-enabled C-H activation of arenes have led us to identify the catalytically active species and a transition state model that explains the exceptional activity and selectivity of these catalysts. These findings are expected to be highly useful for further method development using this powerful class of catalysts.

Sterically Controlled C-H Olefination of Heteroarenes.

The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compounds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes have been reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting material. Herein we report a sterically controlled C-H olefination using heteroarenes as the limiting reagent. The method enables the highly C5-selective olefination of a wide range of heteroarenes and is shown to be useful in the context of late-stage functionalization.