Photoredox Activation of Carbon Dioxide for Amino Acid Synthesis in Continuous Flow

Although carbon dioxide (CO2) is highly abundant, its low reactivity has limited its use in chemical synthesis. In particular, methods for carbon–carbon bond formation generally rely on two-electron mechanisms for CO2 activation and require highly activated reaction partners. Alternatively, radical pathways accessed via photoredox catalysis could provide new reactivity under milder conditions. Here we demonstrate the direct coupling of CO2 and amines via the single-electron reduction of CO2 for the photoredox-catalysed continuous flow synthesis of α-amino acids. By leveraging the advantages of utilizing gases and photochemistry in flow, a commercially available organic photoredox catalyst effects the selective α-carboxylation of amines that bear various functional groups and heterocycles. The preliminary mechanistic studies support CO2 activation and carbon–carbon bond formation via single-electron pathways, and we expect that this strategy will inspire new perspectives on using this feedstock chemical in organic synthesis.

Photoredox Activation of SF6 for Fluorination

We report the first practical use of SF6 as a fluorinating reagent in organic synthesis. Photoredox catalysis enables the in situ conversion of SF6, an inert gas, into an active fluorinating species by using visible light. Under these conditions, deoxyfluorination of allylic alcohols is effected with high chemoselectivity and is tolerant of a wide range of functional groups. Application of the methodology in a continuous-flow setup achieves comparable yields to those obtained with a batch setup, while providing drastically increased material throughput of valuable allylic fluoride products.

Highly Regioselective Indoline Synthesis Under Nickel/Photoredox Dual Catalysis

Nickel/photoredox catalysis is used to synthesize indolines in one step from iodoacetanilides and alkenes. Very high regioselectivity for 3-substituted indoline products is obtained for both aliphatic and styrenyl olefins. Mechanistic investigations indicate that oxidation to Ni(III) is necessary to perform the difficult C−N bond-forming reductive elimination, producing a Ni(I) complex, which in turn is reduced to Ni(0). This process serves to further demonstrate the utility of photoredox catalysts as controlled single electron transfer agents in multioxidation state nickel catalysis

Synthesis of Highly Functionalized Polycyclic Quinoxaline Derivatives Using Visible-Light Photoredox Catalysis

A mild and facile method for preparing highly functionalized pyrrolo[1,2-a]quinoxalines and other nitrogen-rich heterocycles, each containing a quinoxaline core or an analogue thereof, has been developed. The novel method features a visible-light-induced decarboxylative radical coupling of ortho-substituted arylisocyanides and radicals generated from phenyliodine(III) dicarboxylate reagents and exhibits excellent functional group compatibility. A wide range of quinoxaline heterocycles have been prepared. Finally, a telescoped preparation of these polycyclic compounds by integration of the in-line isocyanide formation and photochemical cyclization has been established in a three-step continuous-flow system.

Continuous Flow Photocatalysis Enhanced Using an Aluminum Mirror: Rapid and Selective Synthesis of 2’-Deoxy and 2’,3’-Dideoxynucleosides

Many deoxynucleosides have potent effects against viruses and tumors.1 Several have been approved as antiviral and/or anti-cancer drugs, including zidovudine, stavudine, trifluridine, idoxuridine, cladribine and didanosine (Fig. 1). Extraction from natural sources and fermentation processes provide only a limited number of naturally occurring 2′-deoxynucleosides; therefore, chemical approaches for the general synthesis of deoxynucleosides are highly desired.2 A common strategy is the direct SN2 reaction between a 1-chloro-2-deoxyribose derivative and a metalated or silylated nitrogenous base. Drawbacks of this strategy are the costs and stereochemical lability of 1-chloro sugars. Furthermore, the substitution reaction tends to generate a mixture of anomers that are difficult to separate

Visible-Light Photoredox Catalysis in Flow

Photoredox catalysts have recently been used as powerful tools for synthetic chemists to exploit the energy gained by the absorption of low-energy light within the visible spectrum to initiate a variety of organic transformations.1 The development of methods based on the single-electron transfer properties of photoredox catalysts, particularly in the last several years, has represented a shift in models with respect to the way synthetic chemists consider both photochemistry and redox manipulations of organic molecules.2–4In addition, the advent of new technologies has enabled chemists to conduct reactions with greater efficiency than ever before. Among these new technologies is the development and wide implementation of flow reactors.5, 6 Conducting transformations in flow has many advantages compared to the more traditional batch reactions, in particular: a more predictable reaction scale-up, decreased safety hazards, and improved reproducibility. In addition, for photochemical transformations, the high surface-area-to-volume ratios typical of flow reactors allow for more efficient irradiation of a reaction mixture.7 Due to this feature, we reasoned that a mesofluidic photochemical flow reactor would be amenable to our group’s ongoing study of visible-light-induced organic transformations mediated by photoredox catalysts.

Continuous Photochemical Generation of Catalytically Active [CpRu]+ Complexes from CpRu(η6-C6H6)PF6

Inter- and intramolecular ene–yne coupling reactions catalyzed by a species generated in situ via photolysis of CpRu(η6-C6H6)PF6—an inexpensive, readily available, and shelf-stable complex—have been demonstrated under conditions of continuous flow. Importantly, the catalyst can be recovered quantitatively at the end of the reaction. Various functional groups are tolerated by the reaction, which affords skipped diene products in high yields.