Phenols are important starting materials, intermediates, and functional elements of a very broad range of chemicals and materials. They are large-volume products of benzene oxidation and are increasingly available from biomass. Investment in methodologies that improve the efficiency of their use can have both immediate and future impacts on chemical upgrading. This review summarizes recent phenol-directed C–H functionalization reactions, which provide efficient increases in molecular complexity. Catalytic methodologies play an increasingly important role in addressing long-standing challenges of chemo- and regioselectivity, setting the stage for increased use of phenols in fine-chemical synthesis. We discuss these advances while underscoring persistent challenges, with the goal of motivating increased interest in this versatile functional group.

The oxidation of phenols is the subject of extensive investigation, but there are few catalytic aerobic examples that are chemo- and regioselective. Here we describe conditions for the ortho-oxygenation or oxidative coupling of phenols under copper (Cu)-catalyzed aerobic conditions that give rise to ortho-quinones, biphenols or benzoxepines. We demonstrate that each product class can be accessed selectively by the appropriate choice of Cu(I) salt, amine ligand, desiccant and reaction temperature. In addition, we evaluate the effects of substituents on the phenol and demonstrate their influence on selectivity between ortho-oxygenation and oxidative coupling pathways. These results create an important precedent of catalyst control in the catalytic aerobic oxidation of phenols and set the stage for future development of catalytic systems and mechanistic investigations.

The importance of aromatic C-O, C-N, and C-S bonds necessitates increasingly efficient strategies for their formation. Herein, we report a biomimetic approach that converts phenolic C-H bonds into C-O, C-N, and C-S bonds at the sole expense of reducing dioxygen (O2) to water (H2O). Our method hinges on a regio- and chemoselective copper-catalyzed aerobic oxygenation to provide ortho-quinones. ortho-Quinones are versatile intermediates, whose direct catalytic aerobic synthesis from phenols enables a mild and efficient means of synthesizing polyfunctional aromatic rings.

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. This complex is the resting state of the Cu catalyst during turnover at room temperature. A mechanistic study of the formation of this complex at low temperatures demonstrates that the oxygenation pathway mimics the dinuclear Cu enzyme tyrosinase by involving a dinuclear side-on peroxodicopper(II) oxidant. Unlike the enzyme, however, the rate-limiting step of the ortho-oxygenation reaction is the self-assembly of the oxidant from Cu(I) and O2. We provide details for all steps in the cycle and demonstrate that turnover is contingent upon proton-transfer events that are mediated by a slight excess of ligand. Finally, our knowledge of the reaction mechanism can be leveraged to diversify the reaction outcome. Thus, uncoupled ortho-quinones are favored in polar, coordinating media, highlighting unusually high levels of chemoselectivity for a catalytic aerobic oxidation of a phenol.

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. By judicious modification of substrates with a photoreactive group, PAL creates a covalent crosslink between a substrate and its biological target following UV‐irradiation. Among the commonly employed photoreactive groups, diazirines have emerged as the gold standard. In this Minireview, recent developments in the field of diazirine‐based photoaffinity labeling will be discussed, with emphasis being placed on their applications in chemical proteomic studies.

A concise synthesis of rubioncolin B is described, which features an unprecedented intramolecular Diels−Alder reaction involving an ortho-quinone methide and a naphthofuran moiety. The ortho-quinone methide is generated through a surprisingly facile tautomerization of a para-quinone.

Biomimetic synthesis is an attempt to assemble natural products along biosynthetic lines without recourse to the full enzymatic machinery of nature. We exemplify this with a total synthesis of exiguamine A and the newly isolated natural product exiguamine B. The most noteworthy feature of this work is an oxidative endgame drawing from the complex chemistry of catecholamines, which allows for ready access to a new class of nanomolar indoleamine-2,3-dioxygenase inhibitors.

A robust route to 2,4-disubstituted pyrrole heterocycles relying upon a cascade reaction is reported. The reaction benefits from operational simplicity: it is air and moisture tolerant and is performed at ambient temperature. Control over the reaction conditions provides ready access to isopyrroles, 2,3,4-trisubstituted pyrroles and 3-substituted pyrollidin-2-ones.The finite nature of chemical feedstocks coupled with the negative impacts of manufacturing waste streams necessitates the continued development of increasingly efficient processes for the preparation of valuable synthetic building blocks. 1 In this regard, our group has demonstrated that simple addition reactions between differentially substituted alkynes can be interfaced with subsequent isomerizations to generate functional molecules while upholding high levels of atom-economy. 2 These one-pot reactions benefit from the ability to conduct multiple chemical transformations in a single reaction vessel, providing their intended target while minimizing waste associated with traditional isolation and purification protocols. 3 We envisioned that such a strategy could be applied to the efficient production of valuable pyrrole heterocycles from alkyne starting materials (Scheme 1). 4 The addition of terminal alkyne 2 to suitably activated propargyl amine 1 under alkyne cross-coupling conditions 5 would result in ynenoate 3, whose isomerization via a 5-endo-dig cyclization and tautomerization would then provide pyrrole 5 (Scheme 1). 6 While this sequence represents an efficient, isohypsic 7 entry into 2,4-disubstituted pyrroles, 8 we anticipated that intermediates 3 and 4 could serve as strategic points of product diversification if suitable conditions could be found for their selective preparation. 9 In this regard, we viewed the design of a flexible route to topologically varied 5-membered nitrogen heterocycles as an intriguing challenge for atom-economic reaction design. 10 We anticipated that electron-deficient propargyl amine 1 11 would serve as a suitable acceptor in a cross-alkyne coupling reaction. It should be noted that propargyl amides similar to 1 are prone to 5-endo-dig cyclization, affording the corresponding oxazole heterocycle. 12 In this regard, the current method provides a novel avenue of reactivity for these versatile building blocks while avoiding such an isomerization process.Initial investigations employing phenyl acetylene (2a) as the donor alkyne with toluene as the solvent 13 revealed that product distributions depend on the ratio of Pd(OAc) 2 to the tris(2,6-dimethoxyphenyl)phosphine (TDMPP) ligand (Table 1) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript equimolar amount of ligand and metal cleanly afforded ynenoate 3a as a single geometrical isomer (entry 1), whereas decreasing the amount of TDMPP resulted in competitive formation of isopyrrole 4a (entries 2 and 3). Importantly, pyrrole formation was not observed under the reaction conditions and increasing either the reaction time or...