Radical C(sp3)-H functionalization and cross-coupling reactions.

C─H functionalization reactions are playing an increasing role in the preparation and modification of complex organic molecules, including pharmaceuticals, agrochemicals, and polymer precursors. Radical C─H functionalization reactions, initiated by hydrogen-atom transfer (HAT) and proceeding via open-shell radical intermediates, have been expanding rapidly in recent years. These methods introduce strategic opportunities to functionalize C(sp3)─H bonds. Examples include synthetically useful advances in radical-chain reactivity and biomimetic radical-rebound reactions. A growing number of reactions, however, proceed via "radical relay" whereby HAT generates a diffusible radical that is functionalized by a separate reagent or catalyst. The latter methods provide the basis for versatile C─H cross-coupling methods with diverse partners. In the present review, highlights of recent radical-chain and radical-rebound methods provide context for a survey of emerging radical-relay methods, which greatly expand the scope and utility of intermolecular C(sp3)─H functionalization and cross coupling.

Chemical and Electrochemical O2 Reduction on Earth-Abundant M-N-C Catalysts and Implications for Mediated Electrolysis.

M-N-C catalysts, incorporating non-precious-metal ions (e.g. M = Fe, Co) within a nitrogen-doped carbon support, have been the focus of broad interest for electrochemical O2 reduction and aerobic oxidation reactions. The present study explores the mechanistic relationship between the O2 reduction mechanism under electrochemical and chemical conditions. Chemical O2 reduction is investigated via the aerobic oxidation of a hydroquinone, in which the O-H bonds supply the protons and electrons needed for O2 reduction to water. Mechanistic studies have been conducted to elucidate whether the M-N-C catalyst couples two independent half-reactions (IHR), similar to electrode-mediated processes, or mediates a direct inner-sphere reaction (ISR) between O2 and the organic molecule. Kinetic data support the latter ISR pathway. This conclusion is reinforced by rate/potential correlations that reveal significantly different Tafel slopes, implicating different mechanisms for chemical and electrochemical O2 reduction.

Benzylic C-H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas.

C(sp3)-H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp3)-H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C-H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2'-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, and N-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C-H functionalization/cross-coupling in drug discovery.

Site-Selective Copper-Catalyzed Azidation of Benzylic C-H Bonds.

Site selectivity represents a key challenge for non-directed C-H functionalization, even when the C-H bond is intrinsically reactive. Here, we report a copper-catalyzed method for benzylic C-H azidation of diverse molecules. Experimental and density functional theory studies suggest the benzyl radical reacts with a CuII-azide species via a radical-polar crossover pathway. Comparison of this method with other C-H azidation methods highlights its unique site selectivity, and conversions of the benzyl azide products into amine, triazole, tetrazole, and pyrrole functional groups highlight the broad utility of this method for target molecule synthesis and medicinal chemistry.

Efficient electrochemical synthesis of robust, densely functionalized water soluble quinones.

Conjugate addition of thiols to benzoquinones has been coupled to in situ electrochemical oxidation of the resulting hydroquinone to enable full substitution of quinone C-H bonds. The sulfonated thioether-substituted quinones exhibit high solublity and stability in aqueous solution and have redox potentials ranging from 440-750 mV vs. SHE. The electrosynthetic protocol is effective on >100 g scale.

The mechanism of the triple aryne-tetrazine reaction cascade: theory and experiment.

This article describes an experimental and computational investigation on the possible aryne reactivity modes in the course of the reaction of two highly energetic molecules, an aryne and a 1,2,4,5-tetrazine. Beyond the triple aryne-tetrazine (TAT) reaction, it was observed that combinations of several reactivity modes afford several heterocyclic compounds. Density Functional Theory (DFT) calculations of competition between a second Diels-Alder reaction and the nucleophilic addition pathways indicates the latter to be more favorable. Crossover experiments and computational study of the proton transfer step reveal that the reaction proceeds intermolecularly with the assistance of a water molecule, rather than intramolecularly. The resulting enamine intermediate was found to undergo either a stepwise formal [2 + 2] or [4 + 2] cycloaddition, and their energetic profiles were compared against each other. Isolation of an ene-product and a rearranged product shows the potential competition with oxidation/desaturation. These studies show how multiple arynes react with a highly reactive starting material and provide guidance for future applications of aryne-based multicomponent cascade reactions.

Aryne Compatible Solvents are not Always Innocent.

Arynes are important and versatile intermediates in a variety of transformations. Commonly used solvents for aryne chemistry include acetonitrile and dichloromethane. Although rarely reported, the reactive nature of aryne intermediates makes them prone to side reactions, which sometimes involve solvent participation. Acetonitrile and dichloromethane are not always innocent solvents and can participate in aryne-based reactions. These results are presented in the context of ongoing mechanistic investigations of the triple aryne-tetrazine reaction.

Bridgehead-Substituted Triptycenes for Discovery of Nucleic Acid Junction Binders.

Recently, the utility of triptycene as a scaffold for targeting nucleic acid three-way junctions was demonstrated. A rapid, efficient route for the synthesis of bridgehead-substituted triptycenes is reported, in addition to solid-phase diversification to a new class of triptycene peptides. The triptycene peptides were evaluated for binding to a d(CAG)·(CTG) repeat DNA junction exhibiting potent affinities. The bridgehead-substituted triptycenes provide new building blocks for rapid access to diverse triptycene ligands with novel architectures.

Synthesis of 9-Substituted Triptycene Building Blocks for Solid-Phase Diversification and Nucleic Acid Junction Targeting.

Triptycenes have been shown to bind nucleic acid three-way junctions, but rapid and efficient methods to diversify the triptycene core are lacking. An efficient synthesis of a 9-substituted triptycene scaffold is reported that can be used as a building block for solid-phase peptide synthesis and rapid diversification. The triptycene building block was diversified to produce a new class of tripeptide-triptycenes, and their binding abilities toward d(CAG)·(CTG) repeat junctions were investigated.

Triple Aryne-Tetrazine Reaction Enabling Rapid Access to a New Class of Polyaromatic Heterocycles.

One of the most challenging goals of modern synthetic chemistry is to develop multi-step reactions for rapid and efficient access to complex molecules. We report a triple aryne-tetrazine reaction that enables rapid access to a new class of polyaromatic heterocycles. This new reaction, which couples diverse reactivity modes between simple aryne and tetrazine starting materials, proceeds in a single operation and takes less than 5 minutes in air with no metal catalyst.

Aryl hydrazide beyond as surrogate of aryl hydrazine in the Fischer indolization: the synthesis of N-Cbz-indoles, N-Cbz-carbazoles, and N,N'-bis-Cbz-pyrrolo[2,3-f]indoles.

Aryl hydrazides underwent the Fischer indolization reactions, while the N-carbamate group(s) remained intact to directly provide N-Cbz-indoles. This new method allowed the synthesis of various N-Cbz-carbazoles and N,N'-bis-Cbz-pyrrolo[2,3-f]indoles.