A para- to meta-isomerization of phenols.

Phenols and their derivatives are ubiquitous in nature and critically important industrial chemicals. Their properties are intimately linked to the relative substitution pattern of the aromatic ring, reflecting well-known electronic effects of the OH group. Because of these ortho-, para-directing effects, meta-substituted phenols have historically been more difficult to synthesize.

Mechanisms for radical reactions initiating from -hydroxyphthalimide esters.

Due to their ease of preparation, stability, and diverse reactivity, -hydroxyphthalimide (NHPI) esters have found many applications as radical precursors. Mechanistically, NHPI esters undergo a reductive decarboxylative fragmentation to provide a substrate radical capable of engaging in diverse transformations. Their reduction via single-electron transfer (SET) can occur under thermal, photochemical, or electrochemical conditions and can be influenced by a number of factors, including the nature of the electron donor, the use of Brønsted and Lewis acids, and the possibility of forming charge-transfer complexes.

Indole-5,6-quinones display hallmark properties of eumelanin.

Melanins are ubiquitous biopolymers produced from phenols and catechols by oxidation. They provide photoprotection, pigmentation and redox activity to most life forms, and inspire synthetic materials with desirable optical, electronic and mechanical properties. The chemical structures of melanins remain elusive, however, creating uncertainty about their roles, and preventing the design of synthetic mimics with tailored properties.

A Bioinspired Synthesis of 1,4-Benzothiazines by Selective Addition of Sulfur Nucleophiles to -Quinones.

Herein, we report a bioinspired approach to the synthesis of 1,4-benzothiazines by drawing inspiration from the biosynthesis of pheomelanin pigments (pheomelanogenesis). In this context, general conditions for the regioselective coupling reaction between -quinones and thiols were developed. The mild conditions proved amenable to a wide scope of both thiol and -quinone coupling partners while simultaneously suppressing redox-exchange.

Dearomatization of Biaryls through Polarity Mismatched Radical Spirocyclization.

Dearomatization reactions involving radical cyclizations can facilitate the synthesis of complex polycyclic systems that find applications in medicinal chemistry and natural product synthesis. Here we employ redox-neutral photocatalysis to affect a radical spirocyclization that transforms biaryls into spirocyclic cyclohexadienones under mild reaction conditions. In a departure from previously reported methods, our work demonstrates the polarity mismatched addition of a nucleophilic radical to an electron rich arene, and allows the regioselective synthesis of 2,4- or 2,5-cyclohexadienones with broad functional group tolerance.

Mimicking oxidative radical cyclizations of lignan biosynthesis using redox-neutral photocatalysis.

Oxidative cyclizations create many unique chemical structures that are characteristic of biologically active natural products. Many of these reactions are catalysed by 'non-canonical' or 'thwarted' iron oxygenases and appear to involve long-lived radicals. Mimicking these biosynthetic transformations with chemical equivalents has been a long-standing goal of synthetic chemists but the fleeting nature of radicals, particularly under oxidizing conditions, makes this challenging.

Total Synthesis of ()-Cularine via Nucleophilic Substitution on a Catechol.

Catechols are part of many essential chemicals and are valuable, typically nucleophilic intermediates used in synthesis. Here we describe an unexpected transformation in which they play the role of the electrophile in a formal nucleophilic aromatic substitution. We made this discovery while studying a seven-membered dioxepin ring formation during a synthesis of the benzyltetrahydroisoquinoline ()-cularine.

Synthesis of 1,2-Dihydroisoquinolines by a Modified Pomeranz-Fritsch Cyclization.

Isoquinolines () and their derivatives are present in many natural products and biologically active small molecules. Herein, we report a modified procedure for the classical Pomeranz-Fritsch protocol, which expands the scope of 1,2-dihydroisoquinoline () products. 1,2- are an attractive branch point for the synthesis of , but because of their innate reactivity, they have remained difficult to prepare.

Total Synthesis of (,)-Tetramethylmagnolamine via Aerobic Desymmetrization.

We describe a concise synthesis of the pseudodimeric tetrahydroisoqunoline alkaloid (,)-tetramethylmagnolamine by a catalytic aerobic desymmetrization of phenols. Desymmetrization reactions increase molecular complexity with high levels of efficiency, but those that do so by aerobic oxidation are uncommon. Our conditions employ molecular oxygen as an oxygen atom transfer agent and a formal acceptor of hydrogen, enabling two mechanistically distinct aromatic C-H oxygenation reactions with high degrees of selectivity.

Recent Applications of Diazirines in Chemical Proteomics.

The elucidation of substrate-protein interactions is an important component of the drug development process. Due to the complexity of native cellular environments, elucidating these fundamental biochemical interactions remains challenging. Photoaffinity labeling (PAL) is a versatile technique that can provide insight into ligand-target interactions.

A Bioinspired Synthesis of Polyfunctional Indoles.

Polyfunctional indoles bearing substituents at C5 and C6 are prevalent in natural products, pharmaceuticals, agrochemicals, and materials. Owing to the remoteness of the C5 and C6 positions, indoles of this family can be difficult to prepare, and often require multistep syntheses. Herein, we describe a concise process that converts simple derivatives of tyrosine into 5,6-difunctionalized indoles by direct oxidation of C-H, N-H, and O-H bonds.

Selectivity in the Aerobic Dearomatization of Phenols: Total Synthesis of Dehydronornuciferine by Chemo- and Regioselective Oxidation.

We describe a selective aerobic oxidation of meta-biaryl phenols that enables rapid access to functionalized phenanthrenes. Aerobic oxidations attract interest due to their efficiency, but remain underutilized in complex molecule settings due to challenges of selectivity. We discuss these issues in the context of Cu catalysis, and highlight the advantages of confining oxygen activation and substrate oxidation to the catalyst's inner-coordination sphere.

Stopping Aerobic Oxidation in Its Tracks: Chemoselective Synthesis of Benzaldehydes from Methylarenes.

A practical and elegant solution to the long-standing challenge of methylarene partial oxidation has recently been provided by Pappo and co-workers who devised a catalytic aerobic route to benzaldehydes. The solution hinges on the unique hydrogen-bonding capacity of hexafluoroisopropanol, which prevents overoxidation of the aldehyde to the carboxylic acid.

A chlorine-free protocol for processing germanium.

Replacing molecular chlorine and hydrochloric acid with less energy- and risk-intensive reagents would markedly improve the environmental impact of metal manufacturing at a time when demand for metals is rapidly increasing. We describe a recyclable quinone/catechol redox platform that provides an innovative replacement for elemental chlorine and hydrochloric acid in the conversion of either germanium metal or germanium dioxide to a germanium tetrachloride substitute. Germanium is classified as a "critical" element based on its high dispersion in the environment, growing demand, and lack of suitable substitutes.

Second-Order Biomimicry: In Situ Oxidative Self-Processing Converts Copper(I)/Diamine Precursor into a Highly Active Aerobic Oxidation Catalyst.

A homogeneous Cu-based catalyst system consisting of [Cu(MeCN)]PF, ,'-di--butylethylenediamine (DBED), and -(,-dimethylamino)pyridine (DMAP) mediates efficient aerobic oxidation of alcohols. Mechanistic study of this reaction shows that the catalyst undergoes an in situ oxidative self-processing step, resulting in conversion of DBED into a nitroxyl that serves as an efficient cocatalyst for aerobic alcohol oxidation. Insights into this behavior are gained from kinetic studies, which reveal an induction period at the beginning of the reaction that correlates with the oxidative self-processing step, EPR spectroscopic analysis of the catalytic reaction mixture, which shows the buildup of the organic nitroxyl species during steady state turnover, and independent synthesis of oxygenated DBED derivatives, which are shown to serve as effective cocatalysts and eliminate the induction period in the reaction.

Synthesis of ortho-Azophenols by Formal Dehydrogenative Coupling of Phenols and Hydrazines or Hydrazides.

Azophenols are important chromophores and reagents in organic synthesis, with applications as pigments and molecular switches. Here, we describe a catalytic aerobic process that couples phenols and hydrazines or hydrazides for their synthesis. The key aromatic C-N bond is formed by condensation between the hydrazine or hydrazide and an ortho-quinone, which triggers a redox-isomerization to install the azo-functionality.

Simple Copper Catalysts for the Aerobic Oxidation of Amines: Selectivity Control by the Counterion.

We describe the use of simple copper-salt catalysts in the selective aerobic oxidation of amines to nitriles or imines. These catalysts are marked by their exceptional efficiency, operate at ambient temperature and pressure, and allow the oxidation of amines without expensive ligands or additives. This study highlights the significant role counterions can play in controlling selectivity in catalytic aerobic oxidations.

Asymmetric synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives sequential palladium and copper catalysis.

We present a full account detailing the development of a sequential catalysis strategy for the synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives. A palladium-catalyzed cross coupling of terminal alkyne donors with acetylenic ester, ketone, and sulfone acceptors generates stereodefined enynes in high yield. These compounds are engaged in an unprecedented, regio- and enantioselective copper-catalyzed conjugate reduction.

Synthesis of a 1,3-Bridged Macrobicyclic Enyne via Chemoselective Cycloisomerization Using Palladium-Catalyzed Alkyne-Alkyne Coupling.

A unique intramolecular Pd-catalyzed alkyne-alkyne coupling is presented. This transformation generates a strained, 1,3-bridged, macrocyclic enyne. The process was readily executed on gram scale, and the structure of the product was elucidated via X-ray crystallographic analysis.

A Catalyst-Controlled Aerobic Coupling of ortho-Quinones and Phenols Applied to the Synthesis of Aryl Ethers.

ortho-Quinones are underutilized six-carbon-atom building blocks. We herein describe an approach for controlling their reactivity with copper that gives rise to a catalytic aerobic cross-coupling with phenols. The resulting aryl ethers are generated in high yield across a broad substrate scope under mild conditions.

A bio-inspired synthesis of oxindoles by catalytic aerobic dual C-H functionalization of phenols.

Nitrogen-containing heterocycles are fundamentally important to the function of pharmaceuticals, agrochemicals and materials. Herein, we report a bio-inspired approach to the synthesis of oxindoles, which couples the energetic requirements of dehydrogenative C-N bond formation to the reduction of molecular oxygen (O). Our method is inspired by the biosynthesis of melanin pigments (melanogenesis), but diverges from the biosynthetic polymerization.

Redox-promoted associative assembly of metal-organic materials.

We develop an associative synthesis of metal-organic materials that combines solid-state metal oxidation and coordination-driven self-assembly into a one-step, waste-free transformation. The methodology hinges on the unique reactivity of -quinones, which we introduce as versatile oxidants for mechanochemical synthesis. Our strategy opens a previously unexplored route to paramagnetic metal-organic materials from elementary metals.

A Biomimetic Mechanism for the Copper-Catalyzed Aerobic Oxygenation of 4-tert-Butylphenol.

Controlling product selectivity during the catalytic aerobic oxidation of phenols remains a significant challenge that hinders reaction development. This work provides a mechanistic picture of a Cu-catalyzed, aerobic functionalization of phenols that is selective for phenoxy-coupled ortho-quinones. We show that the immediate product of the reaction is a Cu(II)-semiquinone radical complex and reveal that ortho-oxygenation precedes oxidative coupling.

A TEMPO-free copper-catalyzed aerobic oxidation of alcohols.

The copper-catalyzed aerobic oxidation of primary and secondary alcohols without an external N-oxide co-oxidant is described. The catalyst system is composed of a Cu/diamine complex inspired by the enzyme tyrosinase, along with dimethylaminopyridine (DMAP) or N-methylimidazole (NMI). The Cu catalyst system works without 2,2,6,6-tetramethyl-l-piperidinoxyl (TEMPO) at ambient pressure and temperature, and displays activity for un-activated secondary alcohols, which remain a challenging substrate for catalytic aerobic systems.

A bio-inspired total synthesis of tetrahydrofuran lignans.

Lignan natural products comprise a broad spectrum of biologically active secondary metabolites. Their structural diversity belies a common biosynthesis, which involves regio- and chemoselective oxidative coupling of propenyl phenols. Attempts to replicate this oxidative coupling have revealed significant challenges for controlling selectivity, and these challenges have thus far prevented the development of a unified biomimetic route to compounds of the lignan family.