Visible-light photocatalysis has evolved over the last decade into a widely used method in organic synthesis. Photocatalytic variants have been reported for many important transformations, such as cross-coupling reactions, α-amino functionalizations, cycloadditions, ATRA reactions, or fluorinations. To help chemists select photocatalytic methods for their synthesis, we compare in this Review classical and photocatalytic procedures for selected classes of reactions and highlight their advantages and limitations. In many cases, the photocatalytic reactions proceed under milder reaction conditions, typically at room temperature, and stoichiometric reagents are replaced by simple oxidants or reductants, such as air, oxygen, or amines. Does visible-light photocatalysis make a difference in organic synthesis? The prospect of shuttling electrons back and forth to substrates and intermediates or to selectively transfer energy through a visible-light-absorbing photocatalyst holds the promise to improve current procedures in radical chemistry and to open up new avenues by accessing reactive species hitherto unknown, especially by merging photocatalysis with organo- or metal catalysis.

Visible-Light Photocatalysis: Does It Make a Difference in Organic Synthesis?

The advent of modern C–H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C–H bonds of drug leads as points of diversification for generating new analogs. LSF approaches offer the promise of rapid exploration of structure activity relationships (SAR), the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. This review details a toolbox of intermolecular C–H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations. In addition, a number of examples illustrate how LSF approaches have been used to impact actual drug discovery and chemical biology efforts.

The medicinal chemist's toolbox for late stage functionalization of drug-like molecules

For green and sustainable chemistry, molecular oxygen is considered as an ideal oxidant due to its natural, inexpensive, and environmentally friendly characteristics, and therefore offers attractive academic and industrial prospects. This critical review introduces the recent advances over the past 5 years in transition-metal catalyzed reactions using molecular oxygen as the oxidant. This review highlights the scope and limitations, as well as the mechanisms of these oxidation reactions (184 references).

Recent advances in transition-metal catalyzed reactions using molecular oxygen as the oxidant

Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This perspective attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations.

Dialkylbiaryl phosphines in Pd-catalyzed amination: a user's guide

Research and industrial interest in radical C–H activation/radical cross-coupling chemistry has continuously grown over the past few decades. These reactions offer fascinating and unconventional approaches toward connecting molecular fragments with high atom- and step-economy that are often complementary to traditional methods. Success in this area of research was made possible through the development of photocatalysis and first-row transition metal catalysis along with the use of peroxides as radical initiators. This Review provides a brief and concise overview of the current status and latest methodologies using radicals or radical cations as key intermediates produced via radical C–H activation. This Review includes radical addition, radical cascade cyclization, radical/radical cross-coupling, coupling of radicals with M–R groups, and coupling of radical cations with nucleophiles (Nu).

Recent Advances in Radical C-H Activation/Radical Cross-Coupling.

Transformations that selectively functionalize aliphatic C–H bonds hold significant promise to streamline complex molecule synthesis. Despite the potential for site-selective C–H functionalization, few intermolecular processes of preparative value exist. Herein, we report an approach to unactivated, aliphatic C–H bromination using readily available N-bromoamide reagents and visible light. These halogenations proceed in useful chemical yields, with substrate as the limiting reagent. The site selectivities of these radical-mediated C–H functionalizations are comparable (or superior) to the most selective intermolecular C–H functionalizations known. With the broad utility of alkyl bromides as synthetic intermediates, this convenient approach will find general use in chemical synthesis.

Site-Selective Aliphatic C–H Bromination Using N-Bromoamides and Visible Light

Cycloadditions, such as the [4+2] Diels-Alder reaction to form six-membered rings, are among the most powerful and widely used methods in synthetic chemistry. The analogous [2+2] alkene cycloaddition to synthesize cyclobutanes is kinetically accessible by photochemical methods, but the substrate scope and functional group tolerance are limited. Here, we report iron-catalyzed intermolecular [2+2] cycloaddition of unactivated alkenes and cross cycloaddition of alkenes and dienes as regio- and stereoselective routes to cyclobutanes. Through rational ligand design, development of this base metal-catalyzed method expands the chemical space accessible from abundant hydrocarbon feedstocks.

http://science.sciencemag.org/content/sci/349/6251/960.full.pdf

Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes

The dioxygenation of alkenes using molecular oxygen and a simple hydroxamic acid derivative has been achieved. The reaction system consists of readily prepared methyl N-hydroxy-N-phenylcarbamate and molecular oxygen with a radical initiator, offering an alternative to common dioxygenation processes catalyzed by precious transition metals. This transformation capitalizes on the unique reactivity profile of hydroxamic acid derivatives in radical-mediated alkene addition processes.

Metal-free, aerobic dioxygenation of alkenes using simple hydroxamic acid derivatives.

A radical-mediated approach to metal-free alkene oxyamination is described. This method capitalizes on the unique reactivity of the amidoxyl radical in alkene additions to furnish a general difunctionalization using simple diisopropyl azodicarboxylate (DIAD) as a radical trap. This protocol capitalizes on the intramolecular nature of the process, providing single regioisomers in all cases. Difunctionalizations of cyclic alkenes provide trans oxyamination products inaccessible using current methods with high levels of stereoselectivity, complementing cis-selective oxyamination processes.

Metal-free oxyaminations of alkenes using hydroxamic acids.

Methods for achieving the vicinal difunctionalization of alkenes greatly facilitate the preparation of functionalized organic compounds. Examples of useful transformations include alkene dioxygenations, aminooxidations, and diaminations, with many notable recent developments employing palladium catalysis. A common drawback to these processes is the use of precious and/or toxic transition-metal catalysts. We report herein a convenient, general method for alkene dioxygenation that utilizes oxygen as an environmentally friendly and inexpensive oxidant, while circumventing the use of metal catalysts. As a persistent triplet diradical in its ground state, molecular oxygen reacts rapidly with carbon-centered radicals. This mode of reactivity was witnessed by Gomberg during his historic studies on the first organic free radical, triphenylmethyl, and is an important step in classical radical autoxidation. Radical oxygenation has proven to be of value in modern organic synthesis, especially in cases where the generation of carbon-centered radicals proceeds in a regioselective manner. For example, radical decarboxylation, dehalogenation, demercuration, and carbocyclization processes have all utilized molecular oxygen to selectively deliver radical oxidation products. During their pioneering work on the fundamental reactivity of amidoxyl radicals with alkenes, Perkins and coworkers observed a single remarkable example of an amidoxyl radical cyclization followed by oxygenation (Scheme 1). While attempting to prepare the highly conjugated stilbene-substituted tert-butyl amidoxyl radical 2, the parent hydroxamic acid 1 underwent spontaneous oxidation and intramolecular cyclization followed by radical oxygenation to deliver hydroperoxide 3 as a mixture of diastereomers. These nitroxyl radicals, which contain electronwithdrawing acyl groups, are destabilized relative to persistent dialkyl nitroxyl radicals (e.g. TEMPO, 2,2,6,6-tetramethylpiperidine 1-oxyl), and can be generated by oxidation of N-aryl or alkyl hydroxamic acids under mild conditions. We envisioned an alkene cyclization with a tethered amidoxyl radical that is formed in situ from readily obtained N-aryl hydroxamic acids, and subsequent reaction with molecular oxygen, as a potentially general approach to the dioxygenation of alkenes (Scheme 2). This strategy utilizes amidoxyl radicals as a substitute for highly reactive alkoxy radicals, and allows the production of vicinal diols by subsequent facile reductive cleavage of the N O bond. Furthermore, this method differentiates the oxygen atom functionality delivered to the alkene, which is difficult using current dioxygenation methods.

Valerie A. Schmidt

Papers

Site-Selective Aliphatic C–H Bromination Using N-Bromoamides and Visible Light

Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes

Metal-free, aerobic dioxygenation of alkenes using simple hydroxamic acid derivatives.

Metal-free oxyaminations of alkenes using hydroxamic acids.

Metal‐Free, Aerobic Dioxygenation of Alkenes Using Hydroxamic Acids