Mechanism of Visible Light-Mediated Alkene Aminoarylation with Arylsulfonylacetamides.

Alkene aminoarylation with arylsulfonylacetamides via a visible-light mediated radical Smiles-Truce rearrangement represents a convenient approach to the privileged arylethylamine pharmacaphore traditionally generated by circuitous, multi-step sequences. Herein, we report detailed synthetic, spectroscopic, kinetic, and computational studies designed to interrogate the proposed mechanism, including the key aryl transfer event. The data are consistent with a rate-limiting 1,4-aryl migration occurring either via a stepwise process involving a radical Meisenheimer-like intermediate or in a concerted fashion dependent on both arene electronics and alkene sterics.

Catalytic intramolecular aminoarylation of unactivated alkenes with aryl sulfonamides.

Arylethylamines are abundant motifs in myriad natural products and pharmaceuticals, so efficient methods to synthesize them are valuable in drug discovery. In this work, we disclose an intramolecular alkene aminoarylation cascade that exploits the electrophilicity of a nitrogen-centered radical to form a C-N bond, then repurposes the nitrogen atom's sulfonyl activating group as a traceless linker to form a subsequent C-C bond. This photoredox catalysis protocol enables the preparation of densely substituted arylethylamines from commercially abundant aryl sulfonamides and unactivated alkenes under mild conditions.

Photochemically derived 1-aminonorbornanes provide structurally unique succinate dehydrogenase inhibitors with and activity.

Agrochemical fungicidal leads have been prepared from photochemically derived 1-aminonorbornane building blocks. The unique 1-aminonorbornane core is generated via direct excitation of a Schiff base precursor, leveraging the -centered radical character of the excited state species to facilitate a series of radical reactions that construct the norbornane core. This process requires no exogenous reagents, only solvent and photons; thus, it represents an exceptionally simple and efficient means of generating the key building blocks.

Arene dearomatization through a catalytic N-centered radical cascade reaction.

Arene dearomatization reactions are an important class of synthetic technologies for the rapid assembly of unique chemical architectures. Herein, we report a catalytic protocol to initiate a carboamination/dearomatization cascade that proceeds through transient sulfonamidyl radical intermediates formed from native sulfonamide N-H bonds leading to 1,4-cyclohexadiene-fused sultams. Importantly, this work demonstrates a facile approach to employ two-dimensional aromatic compounds as modular building blocks to generate richly substituted, three-dimensional compounds.

Exploiting Imine Photochemistry for Masked N-Centered Radical Reactivity.

This report details the development of a masked N-centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1-aminonorbornanes. This process employs the N-centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C-C bonds en route to the norbornane core. Achieving bond-forming reactivity as a function of the N-centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance.

Biosynthesis of an Anti-Addiction Agent from the Iboga Plant.

(-)-Ibogaine and (-)-voacangine are plant derived psychoactives that show promise as treatments for opioid addiction. However, these compounds are produced by hard to source plants, making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (-)-voacangine, and de-esterified voacangine, which is converted to (-)-ibogaine by heating, enabling biocatalytic production of these compounds.

Illuminating Photoredox Catalysis.

Over the past decade, photoredox catalysis has risen to the forefront of synthetic organic chemistry as an indispensable tool for selective small-molecule activation and chemical-bond formation. This cutting-edge platform allows photosensitizers to convert visible light into chemical energy prompting generation of reactive radical intermediates. In this Review, we highlight some of the recent key contributions in the field, including: the impact of the chosen light arrays; promoting fundamental cross-coupling steps; selectively functionalizing aliphatic amines; engaging complementary mechanistic paradigms; and applications in industry.

Advancements in Visible-Light-Enabled Radical C(sp)2-H Alkylation of (Hetero)arenes.

The Minisci reaction, which encompasses the radical C-H alkylation of heteroarenes, has undergone revolutionary development in recent years. The application of photoredox catalysis for alkyl radical generation has given rise to a multitude of methods that feature enhanced functional group tolerance, generality, and operational simplicity. The intent of this short review is to bring readers up to date on this rapidly expanding field.

Functionalized Cyclopentanes via Sc(III)-Catalyzed Intramolecular Enolate Alkylation.

We report herein the intramolecular α--alkylation of unsaturated β-ketoesters which gives rise to highly functionalized cyclopentanes. This strategy is characterized by its operational simplicity, mild reaction conditions and the use of scandium(III) triflate as a Lewis acid catalyst. Of interest, cyclopentanes bearing heterocycles, sites for post reaction functionalization and spirocyclic architectures are accessible with this strategy.

Arylsulfonylacetamides as bifunctional reagents for alkene aminoarylation.

Alkene aminoarylation with a single, bifunctional reagent is a concise synthetic strategy. We report a catalytic protocol for the addition of arylsulfonylacetamides across electron-rich alkenes with complete anti-Markovnikov regioselectivity and excellent diastereoselectivity to provide 2,2-diarylethylamines. In this process, single-electron alkene oxidation enables carbon-nitrogen bond formation to provide a key benzylic radical poised for a Smiles-Truce 1,5-aryl shift.

Radical Chlorodifluoromethylation: Providing a Motif for (Hetero)arene Diversification.

A method for the radical chlorodifluoromethylation of (hetero)arenes using chlorodifluoroacetic anhydride is reported. This operationally simple protocol proceeds under mild photochemical conditions with high functional group compatibility and complements the large body of literature for the trifluoromethylation of (hetero)arenes. Introduction of the chlorodifluoromethyl motif enables rapid diversification to a wide array of aromatic scaffolds.

Metal-binding hydrazone photoswitches for visible light reactivity and variable relaxation kinetics.

The range of applications for photoswitching moieties is diverse, and the ability to design switches with variable photochemical and physical properties is consequently important for realizing their potential. Previously we reported on the photochromism of (E)-N'-(1-(2-hydroxyphenyl)ethylidene)isonicotinohydrazide (HAPI), an aroylhydrazone compound first developed as a transition metal chelator. Herein we report the synthesis of structurally related aroylhydrazone chelators and explore the effect of these modifications on their UVA, UVC and blue light photoreactivity, photostationary state composition, photoisomer thermal stability, and relative iron(iii) binding affinity.

Photochemical Perfluoroalkylation with Pyridine -Oxides: Mechanistic Insights and Performance on a Kilogram Scale.

The direct trifluoromethylation of (hetero)arenes is a process of high importance to the pharmaceutical industry. Many reagents exist for this purpose and have found widespread use in discovery efforts; however, the step-intensive preparation of these reagents and their corresponding cost have resulted in minimal use of these methods in large-scale applications. For the ready transition of direct trifluoromethylation methodologies to large-scale application, the further development of processes utilizing inexpensive CF sources available on a metric ton scale is highly desirable.

Microwave-Assisted Synthesis of Heteroleptic Ir(III)(+) Polypyridyl Complexes.

We report a rapid, one-pot, operationally simple, and scalable preparation of valuable cationic heteroleptic iridium(III) polypyridyl photosensitizers. This method takes advantage of two consecutive microwave irradiation steps in the same reactor vial, avoiding the need for additional reaction purifications. A number of known heteroleptic iridium(III) complexes are prepared in up to 96% yield.