Natural product modification with photoredox catalysis allows for mild, chemoselective access to a wide array of related structures in complex areas of chemical space, providing the possibility for novel structural motifs as well as useful quantities of less abundant congeners. While amine additives have been used extensively as stoichiometric electron donors for photocatalysis, the controlled modification of amine substrates through single-electron oxidation is ideal for the synthesis and modification of alkaloids. Here, we report the conversion of the amine (+)-catharanthine into the natural products (−)-pseudotabersonine, (−)-pseudovincadifformine, and (+)-coronaridine utilizing visible light photoredox catalysis.

The use of photochemical transformations is a powerful strategy that allows for the formation of a high degree of molecular complexity from relatively simple building blocks in a single step. A central feature of all light-promoted transformations is the involvement of electronically excited states, generated upon absorption of photons. This produces transient reactive intermediates and significantly alters the reactivity of a chemical compound. The input of energy provided by light thus offers a means to produce strained and unique target compounds that cannot be assembled using thermal protocols. This review aims at highlighting photochemical transformations as a tool for rapidly accessing structurally and stereochemically diverse scaffolds. Synthetic designs based on photochemical transformations have the potential to afford complex polycyclic carbon skeletons with impressive efficiency, which are of high value in total synthesis.

Harnessing visible light as the driving force for chemical transformations generally offers a more environmentally friendly alternative compared with classical synthetic methodology. The transition metal-based photocatalysts commonly employed in photoredox catalysis absorb efficiently in the visible spectrum, unlike most organic substrates, allowing for orthogonal excitation. The subsequent excited states are both more reducing and more oxidizing than the ground state catalyst and are competitive with some of the more powerful single-electron oxidants or reductants available to organic chemists yet are simply accessed via irradiation. The benefits of this strategy have proven particularly useful in radical chemistry, a field that traditionally employs rather toxic and hazardous reagents to generate the desired intermediates.In this Account, we discuss our efforts to leverage visible light photoredox catalysis in radical-based bond-forming and bond-cleaving events for which few, if any, environmentally benign alternatives exist. Mechanistic investigations have driven our contributions in this field, for both facilitating desired transformations and offering new, unexpected opportunities. In fact, our total synthesis of (+)-gliocladin C was only possible upon elucidating the propensity for various trialkylamine additives to elicit a dual behavior as both a reductive quencher and a H-atom donor. Importantly, while natural product synthesis was central to our initial motivations to explore these photochemical processes, we have since demonstrated applicability within other subfields of chemistry, and our evaluation of flow technologies demonstrates the potential to translate these results from the bench to pilot scale.Our forays into photoredox catalysis began with fundamental methodology, providing a tin-free reductive dehalogenation that exchanged the gamut of hazardous reagents previously employed for such a transformation for visible light-mediated, ambient temperature conditions. Evolving from this work, a new avenue toward atom transfer radical addition (ATRA) chemistry was developed, enabling dual functionalization of both double and triple bonds. Importantly, we have also expanded our portfolio to target clinically relevant scaffolds. Photoredox catalysis proved effective in generating high value fluorinated alkyl radicals through the use of abundantly available starting materials, providing access to libraries of trifluoromethylated (hetero)arenes as well as intriguing gem-difluoro benzyl motifs via a novel photochemical radical Smiles rearrangement. Finally, we discuss a photochemical strategy toward sustainable lignin processing through selective C–O bond cleavage methodology. The collection of these efforts is meant to highlight the potential for visible light-mediated radical chemistry to impact a variety of industrial sectors.

Cleavage of carbon–halogen bonds via either single-electron reduction or atom transfer is a powerful transformation in the construction of complex molecules. In particular, mild, selective hydrodehalogenations provide an excellent follow-up to the application of halogen atoms as directing groups or the utilization of atom transfer radical addition (ATRA) chemistry for the production of hydrocarbons. Here we combine the mechanistic properties of photoredox catalysis and silane-mediated atom transfer chemistry to accomplish the hydrodebromination of carbon–bromide bonds. The resulting method is performed under visible light irradiation in an open vessel and is capable of the efficient reduction of a variety of unactivated alkyl and aryl substrates.Keywords: hydrodehalogenation; photoredox; radical; silane; visible light

Lignin valorization has long been recognized as a sustainable solution for the renewable production of aromatic compounds. Two-step oxidation/reduction strategies, whereby the first oxidation step is required to “activate” lignin systems for controlled fragmentation reactions, have recently emerged as viable routes toward this goal. Herein we describe a catalytic protocol for oxidation of lignin model systems by combining photoredox and Pd catalysis. The developed dual catalytic protocol allowed the efficient oxidation of lignin model substrates at room temperature to afford the oxidized products in good to excellent yields.

The development of a sustainable, carbon-neutral biorefinery has emerged as a prominent scientific and engineering goal of the 21st century. As petroleum has become less accessible, biomass-based carbon sources have been investigated for utility in fuel production and commodity chemical manufacturing. One underutilized biomaterial is lignin; however, its highly crosslinked and randomly polymerized composition have rendered this biopolymer recalcitrant to existing chemical processing. More recently, insight into lignin's molecular structure has reinvigorated chemists to develop catalytic methods for lignin depolymerization. This review examines the development of transition-metal catalyzed reactions and the insights shared between the homogeneous and heterogeneous catalytic systems towards the ultimate goal of valorizing lignin to produce value-added products.

Photoredox catalysis has emerged as a powerful tool for the synthetic chemist to access challenging targets and to generate new structural complexity. This review focuses on the application of this mode of catalysis to arrive at known pharmaceutically active compounds. Within this setting, the growing synergy with other modes of catalysis, such as nickel/photoredox dual catalysis, as well as pioneering examples utilizing continuous flow to transition photoredox catalysis to preparative scale will be highlighted.

A visible light-mediated Smiles rearrangement providing the difluoroethanol motif has been shown to reliably operate on preparative scale up to 100 g of starting material. Mechanistic investigation has revealed the reaction proceeds predominantly via a radical chain process that in some instances can be initiated via visible light or thermal activation in the absence of a photocatalyst. The reaction was demonstrated in continuous flow, with visible light and thermal initiation using a thiophene substrate relevant to pharmaceutical development.

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. Notably, this method is demonstrated to provide the synthetically versatile photosensitizer [Ir(ppy)2(dtbbpy)]PF6 in >1 g quantities in less than 5 h of bench time. We envision this method will help accelerate future developments in visible-light-dependent chemistry.

•Method for the reduction of α-keto ethers amines and sulfides at room temperature using visible light and an Ir(III) photocatalyst.•Reactions run in ethanol with minimal additive loadings.•Lignin model substrates containing the β–O–4 motif were reduced in fair to good yields.Visible light-mediated photoredox catalysis enables the chemoselective reduction of activated carbon–heteroatom bonds as a function of reduction potential. The expansion of the scope of C–X bond reductions towards less activated motifs, such as ethers, amines and sulfides, is important to both organic synthesis and macromolecular degradation method development. In the present report, exploration of photoredox catalysis in alcoholic solvents mediated a decrease in the super-stoichiometric use of iPr2NEt and HCO2H in the reduction of α-keto ethers, amines and sulfides. Additionally, in the absence of fragmentation, CC bond formation was afforded, suggesting an intermediate ketyl radicals are present in these transformations.

The one-pot, three-component, coupling reaction of indoles/pyrroles, dimethyl malonate, and acetic acid was performed using Mn(III) acetate as an oxidant. In the presence of Mn(OAc)3, indole-2, and indole-3-carbonyl compounds were alkylated at the 3- and 2- positions, respectively, with subsequent oxidation and nucleophilic capture occurring at the newly formed benzylic carbon. In contrast, oxidation of 2- and 3-indole carboxylic acids afforded the corresponding 2-oxindol-3-ylidenes and 3-oxindol-2-ylidenes. The reaction conditions, scope, and mechanism are discussed herein.

While the use of visible light to drive chemical reactivity is of high importance to the development of environmentally benign chemical transformations, the concomitant use of a stoichiometric electron donor or acceptor is often required to steer the desired redox behavior of these systems. The low-cost and ubiquity of tertiary amine bases has led to their widespread use as reductive additives in photoredox catalysis. Early use of trialkylamines in this context was focused on their role as reductive excited state quenchers of the photocatalyst, which in turn provides a more highly reducing catalytic intermediate.In this Account, we discuss some of the observations and thought processes that have led from our use of amines as reductive additives to their use as complex substrates and intermediates for natural product synthesis. Early attempts by our group to construct key carbon–carbon bonds via free-radical intermediates led to the observation that some trialkylamines readily behave as efficient hydrogen atom donors under redox-active photochemical conditions. In the wake of in-depth mechanistic studies published in the 1970s, 1980s and 1990s, this understanding has in turn allowed for a systematic approach to the design of a number of photochemical methodologies through rational tuning of the amine component. Minimization of the C–H donicity of the amine additive was found to promote desired C–C bond formation in a number of contexts, and subsequent elucidation of the amine’s redox fate has sparked a reevaluation of the amine’s role from that of reagent to that of substrate.The reactivity of tertiary amines in these photochemical systems is complex, and allows for a number of mechanistic possibilities that are not necessarily mutually exclusive. A variety of combinations of single-electron oxidation, C–H abstraction, deprotonation, and β-scission result in the formation of reactive intermediates such as α-amino radicals and iminium ions. These processes have been explored in depth in the photochemical literature and have resulted in a firm mechanistic grasp of the behavior of amine radical cations in fundamental systems. Harnessing the synthetic potential of these transient species represents an ongoing challenge for the controlled functionalization of amine substrates, because these mechanistic possibilities may result in undesired byproduct formation or substrate decomposition. The presence of tertiary amines in numerous alkaloids, pharmaceuticals, and agrochemicals lends credence to the potential utility of this chemistry in natural product synthesis, and herein we will discuss how these transformations might be controlled for synthetic purposes.

Knowledge of the kinetic behavior of catalysts under synthetically relevant conditions is vital for the efficient use of compounds that mediate important transformations regardless of their composition or driving force. In particular, these data are of great importance to add perspective to the growing number of applications of photoactive transition metal complexes. Here we present kinetic, synthetic, and spectroscopic evidence of the mechanistic behavior of fac-Ir(ppy)3 in a visible light-mediated radical addition to 3-methylindole, demonstrating the instability of fac-Ir(ppy)3 under these conditions. During the reaction, rapid in situ functionalization of the photocatalyst occurs, eventually leading to deactivation. These findings demonstrate a conceivable deactivation process for catalytic single electron reactions in the presence of radicophilic ligands. Attempts to inhibit photocatalyst deactivation through structural modification provide further insight into catalyst selection for a given system of interest.

The enantioselective oxidative C–H functionalization of tetrahydroisoquinoline derivatives is achieved through the merger of photoredox and asymmetric anion-binding catalysis. This combination of two distinct catalysis concepts introduces a potentially general approach to asymmetric transformations in oxidative photocatalysis.

Catalytic radical-based domino reactions represent important advances in synthetic organic chemistry. Their development benefits synthesis by providing atom- and step-economical methods to complex molecules. Intricate combinations of radical, cationic, anionic, oxidative/reductive, and transition metal mechanistic steps result in cyclizations, additions, fragmentations, ring-expansions, and rearrangements. This Perspective summarizes recent developments in the field of catalytic domino processes.Keywords: cascade; domino; photoredox; radical; tandem; transition metal

We report a detailed investigation into the application of visible light-mediated photocatalysis to a challenging bond construction in a complex pharmaceutical target. The optimized reaction allowed the direct coupling of N-methylmorpholine with an unfunctionalized pyridazine in good yield and selectivity, and with high purity of the product isolated via crystallization. The reaction also facilitated the expedient synthesis of a range of analogues via the use of other commercially available N-methyl substituted tertiary amines, and therefore it represents an attractive tool for medicinal chemistry. Furthermore, a number of other interesting photoredox reactions were discovered during the course of this investigation, such as a formal methylation reaction via C–N bond cleavage, functionalization of C–H bonds alpha to amides, and a visible light-mediated iminium ion reduction.

The development of a room-temperature lignin degradation strategy consisting of a chemoselective benzylic oxidation with a recyclable oxidant ([4-AcNH-TEMPO]BF4) and a catalytic reductive C–O bond cleavage utilizing the photocatalyst [Ir(ppy)2(dtbbpy)]PF6 is described. This system was tested on relevant lignin model substrates containing β-O-4 linkages to generate fragmentation products in good to excellent yields.

A tandem dienone photorearrangement–cycloaddition (DPC) reaction of novel cyclohexadienone substrates tethered with various 2π and 4π reaction partners resulted in the formation of polycyclic, bridged frameworks. In particular, use of alkynyl ether-tethered substrates led to (3 + 2) cycloaddition to afford strained alkenes which could be further elaborated by intra- and intermolecular cycloaddition chemistry to produce complex, polycyclic chemotypes.

Knowledge of the kinetic behavior of catalysts under synthetically relevant conditions is vital for the efficient use of compounds that mediate important transformations regardless of their composition or driving force. In particular, these data are of great importance to add perspective to the growing number of applications of photoactive transition metal complexes. Here we present kinetic, synthetic, and spectroscopic evidence of the mechanistic behavior of fac-Ir(ppy)3 in a visible light-mediated radical addition to 3-methylindole, demonstrating the instability of fac-Ir(ppy)3 under these conditions. During the reaction, rapid in situ functionalization of the photocatalyst occurs, eventually leading to deactivation. These findings demonstrate a conceivable deactivation process for catalytic single electron reactions in the presence of radicophilic ligands. Attempts to inhibit photocatalyst deactivation through structural modification provide further insight into catalyst selection for a given system of interest.

The enantioselective oxidative C–H functionalization of tetrahydroisoquinoline derivatives is achieved through the merger of photoredox and asymmetric anion-binding catalysis. This combination of two distinct catalysis concepts introduces a potentially general approach to asymmetric transformations in oxidative photocatalysis.

The development of a sustainable, carbon-neutral biorefinery has emerged as a prominent scientific and engineering goal of the 21st century. As petroleum has become less accessible, biomass-based carbon sources have been investigated for utility in fuel production and commodity chemical manufacturing. One underutilized biomaterial is lignin; however, its highly crosslinked and randomly polymerized composition have rendered this biopolymer recalcitrant to existing chemical processing. More recently, insight into lignin's molecular structure has reinvigorated chemists to develop catalytic methods for lignin depolymerization. This review examines the development of transition-metal catalyzed reactions and the insights shared between the homogeneous and heterogeneous catalytic systems towards the ultimate goal of valorizing lignin to produce value-added products.